rs5036

chr17-44261577-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000342.4(SLC4A1):c.166A>G(p.Lys56Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 1,614,042 control chromosomes in the GnomAD database, including 1,705 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (342 hom., cov: 32)
  • Exomes 𝑓: 0.031 (1363 hom.)
• Consequence: SLC4A1 NM_000342.4 missense, splice_region
• Scores: Splicing: ADA: 0.00005328
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 0.337

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002771765).
• BP6: Variant 17-44261577-T-C is Benign according to our data. Variant chr17-44261577-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 17752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44261577-T-C is described in Lovd as [Benign]. Variant chr17-44261577-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.166A>G	p.Lys56Glu	missense_variant, splice_region_variant	4/20	ENST00000262418.12
SLC4A1	XM_011525129.3	c.166A>G	p.Lys56Glu	missense_variant, splice_region_variant	4/19
SLC4A1	XM_011525130.2	c.166A>G	p.Lys56Glu	missense_variant, splice_region_variant	4/18
SLC4A1	XM_005257593.6	c.-30A>G		splice_region_variant, 5_prime_UTR_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.166A>G	p.Lys56Glu	missense_variant, splice_region_variant	4/20	1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.166A>G	p.Lys56Glu	missense_variant, splice_region_variant	4/15	5
SLC4A1	ENST00000471005.5	n.100A>G		splice_region_variant, non_coding_transcript_exon_variant	2/4	3
SLC4A1	ENST00000498270.1	n.447A>G		splice_region_variant, non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7503 AN: 152094 Hom.: 342 Cov.: 32

Gnomad AFR AF: 0.0985

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0643

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.0855

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0416

GnomAD3 exomes AF: 0.0446 AC: 11216 AN: 251446 Hom.: 512 AF XY: 0.0392 AC XY: 5324 AN XY: 135904

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0406

Gnomad EAS exome AF: 0.0702

Gnomad SAS exome AF: 0.0279

Gnomad FIN exome AF: 0.00628

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0306 AC: 44670 AN: 1461830 Hom.: 1363 Cov.: 32 AF XY: 0.0300 AC XY: 21796 AN XY: 727224

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.0393

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.0290

Gnomad4 FIN exome AF: 0.00689

Gnomad4 NFE exome AF: 0.0223

Gnomad4 OTH exome AF: 0.0368

GnomAD4 genome AF: 0.0494 AC: 7514 AN: 152212 Hom.: 342 Cov.: 32 AF XY: 0.0483 AC XY: 3591 AN XY: 74424

Gnomad4 AFR AF: 0.0984

Gnomad4 AMR AF: 0.0643

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.0857

Gnomad4 SAS AF: 0.0301

Gnomad4 FIN AF: 0.00527

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0307 Hom.: 258

Bravo AF: 0.0582

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.102 AC: 450

ESP6500EA AF: 0.0228 AC: 196

ExAC AF: 0.0424 AC: 5152

Asia WGS AF: 0.0730 AC: 255 AN: 3478

EpiCase AF: 0.0225

EpiControl AF: 0.0228

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2020	This variant is associated with the following publications: (PMID: 29396846, 1520883) -

Hereditary spherocytosis type 4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

BAND 3 MEMPHIS Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Autosomal dominant distal renal tubular acidosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

- -

Hemolytic anemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	5.3
Dann	Benign	0.17
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.064	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.1	N;.
REVEL	Benign	0.079
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.072
MPC		0.49
ClinPred		0.0000096	T
GERP RS		3.6
Varity_R		0.26
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs5036; hg19: chr17-42338945; COSMIC: COSV52259857;