chr17-44261625-C-T

Variant names:

• chr17-44261625-C-T
• rs45562031
• NM_000342.4:c.118G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000342.4(SLC4A1):​c.118G>A​(p.Glu40Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,614,150 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 32)
  • Exomes 𝑓: 0.015 (209 hom.)
• Consequence: SLC4A1 NM_000342.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:12
• Conservation: PhyloP100: 0.681
• Publications: 23 publications found

Genes affected

SLC4A1 (HGNC:11027): (solute carrier family 4 member 1 (Diego blood group)) The protein encoded by this gene is part of the anion exchanger (AE) family and is expressed in the erythrocyte plasma membrane, where it functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs. The protein comprises two domains that are structurally and functionally distinct. The N-terminal 40kDa domain is located in the cytoplasm and acts as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane-associated domain contains 12-14 membrane spanning segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II. The encoded protein associates with the red cell membrane protein glycophorin A and this association promotes the correct folding and translocation of the exchanger. This protein is predominantly dimeric but forms tetramers in the presence of ankyrin. Many mutations in this gene are known in man, and these mutations can lead to two types of disease: destabilization of red cell membrane leading to hereditary spherocytosis, and defective kidney acid secretion leading to distal renal tubular acidosis. Other mutations that do not give rise to disease result in novel blood group antigens, which form the Diego blood group system. Southeast Asian ovalocytosis (SAO, Melanesian ovalocytosis) results from the heterozygous presence of a deletion in the encoded protein and is common in areas where Plasmodium falciparum malaria is endemic. One null mutation in this gene is known, resulting in very severe anemia and nephrocalcinosis. [provided by RefSeq, Jul 2008]

SLC4A1 Gene-Disease associations (from GenCC):

• autosomal dominant distal renal tubular acidosis

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary spherocytosis type 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal tubular acidosis, distal, 4, with hemolytic anemia

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• southeast Asian ovalocytosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cryohydrocytosis

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044904858).
• BP6: Variant 17-44261625-C-T is Benign according to our data. Variant chr17-44261625-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17756.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1690/152288) while in subpopulation NFE AF = 0.018 (1224/68002). AF 95% confidence interval is 0.0172. There are 13 homozygotes in GnomAd4. There are 744 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000342.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A1	NM_000342.4	MANE Select	c.118G>A	p.Glu40Lys	missense	Exon 4 of 20	NP_000333.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A1	ENST00000262418.12	TSL:1 MANE Select	c.118G>A	p.Glu40Lys	missense	Exon 4 of 20	ENSP00000262418.6
	SLC4A1	ENST00000399246.3	TSL:5	c.118G>A	p.Glu40Lys	missense	Exon 4 of 15	ENSP00000382190.3
	SLC4A1	ENST00000471005.5	TSL:3	n.52G>A		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1691 AN: 152170 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0105 AC: 2638 AN: 251402 AF XY: 0.0105

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00642

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00896

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0149 AC: 21724 AN: 1461862 Hom.: 209 Cov.: 33 AF XY: 0.0145 AC XY: 10530 AN XY: 727234

African (AFR) AF: 0.00311 AC: 104 AN: 33480

American (AMR) AF: 0.00684 AC: 306 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86258

European-Finnish (FIN) AF: 0.0101 AC: 540 AN: 53418

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0178 AC: 19790 AN: 1111984

Other (OTH) AF: 0.0121 AC: 733 AN: 60396

GnomAD4 genome AF: 0.0111 AC: 1690 AN: 152288 Hom.: 13 Cov.: 32 AF XY: 0.00999 AC XY: 744 AN XY: 74466

African (AFR) AF: 0.00313 AC: 130 AN: 41566

American (AMR) AF: 0.00647 AC: 99 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00904 AC: 96 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1224 AN: 68002

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.0155 Hom.: 50

Bravo AF: 0.0111

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.0108 AC: 1315

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0162

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Jan 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant also known as Band 3 Montefiore occurs in an acidic region of the N-terminus that contains binding sites for aldolase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, denatured hemoglobins, and protein 4.2 (PMID:11049968). Functional studies indicate the alteration results in impaired binding to protein 4.2. Introduction of a positive charge by the E40K mutants may serve to disrupt the acidic protein 4.2-binding surface on cdAE1 (PMID:21039340). In a single case report, this mutation was detected in the homozygous state in a patient reported to have moderate and episodic nonimmune hemolytic anemia coincident with pregnancy and splenomegaly, spherocytosis, and increased osmotic fragility with a 88% decrease in protein 4.2. None of the heterozygous relatives were symptomatic and had a normal RBC membrane protein 4.2 content (PMID:8471774). This alteration is common in Europeans (MAF 1.8%) but is found at low frequencies in almost all other populations in gnomAD. Due to insufficient data available to clearly classify this variant as pathogenic or benign, it is categorized as a variant of uncertain significance.

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC4A1: BP4, BS1, BS2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC4A1 p.Glu40Lys variant was identified in the literature in a female with episodic hemolytic anemia that was homozygous for the p.E40K variant (Rybicki_1993_8471774). The variant was identified in dbSNP (ID: rs45562031), LOVD 3.0 and ClinVar (classified as likely benign by PreventionGenetics and Illumina, as likely pathogenic by Bioinformatics dept., Datar Cancer Genetics Limited, India and as uncertain signifiicance by ARUP Laboratories and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 3038 of 282752 chromosomes (17 homozygous) at a frequency of 0.010744 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2337 of 129084 chromosomes (freq: 0.0181), Other in 90 of 7228 chromosomes (freq: 0.01245), European (Finnish) in 234 of 25114 chromosomes (freq: 0.009318), Latino in 231 of 35438 chromosomes (freq: 0.006518), African in 74 of 24954 chromosomes (freq: 0.002965), South Asian in 63 of 30616 chromosomes (freq: 0.002058) and Ashkenazi Jewish in 9 of 10368 chromosomes (freq: 0.000868), but was not observed in the East Asian population. The p.Glu40 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Mar 19, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33226606, 31723846, 27535533, 27354418, 21039340, 16411779, 9207478, 8471774, 20981092)

Hereditary spherocytosis type 4 Pathogenic:1 Benign:3

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Glu40Lys variant in SLC4A1 has been identified in an individual with a previous splenectomy (PMID: 8471774), but has been identified in >1% of European (non-Finnish) chromosomes and 3 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive spherocytosis.

Apr 15, 1993

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Cryohydrocytosis Pathogenic:1

Jun 23, 2017

Bioinformatics dept., Datar Cancer Genetics Limited, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant distal renal tubular acidosis Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

SLC4A1-related disorder Benign:1

May 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Distal renal tubular acidosis Benign:1

Jun 06, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hemolytic anemia Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.68
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.21
Sift	Benign	0.20	T
Sift4G	Benign	0.49	T
Polyphen		0.059	B
Vest4		0.30
MPC		0.50
ClinPred		0.017	T
GERP RS		1.1
Varity_R		0.12
gMVP		0.21
Mutation Taster		=96/4	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45562031; hg19: chr17-42338993;