17-44259879-C-T

Position:

• chr17-44259879-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000342.4(SLC4A1):​c.539G>A​(p.Arg180His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,046 control chromosomes in the GnomAD database, including 28 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 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (28 hom.)
• Consequence: SLC4A1 NM_000342.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7 O:1
• Conservation: PhyloP100: -0.714

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024107307).
• BP6: Variant 17-44259879-C-T is Benign according to our data. Variant chr17-44259879-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255914.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3, not_provided=1, Benign=1}. Variant chr17-44259879-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 28 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.539G>A	p.Arg180His	missense_variant	7/20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.539G>A	p.Arg180His	missense_variant	7/19		XP_011523431.1
SLC4A1	XM_005257593.6	c.344G>A	p.Arg115His	missense_variant	5/18		XP_005257650.1
SLC4A1	XM_011525130.2	c.539G>A	p.Arg180His	missense_variant	7/18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.539G>A	p.Arg180His	missense_variant	7/20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.539G>A	p.Arg180His	missense_variant	7/15	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 439 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00241

GnomAD3 exomes AF: 0.00342 AC: 860 AN: 251454 Hom.: 2 AF XY: 0.00345 AC XY: 469 AN XY: 135904

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00962

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00490

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00479 AC: 7003 AN: 1461846 Hom.: 28 Cov.: 33 AF XY: 0.00475 AC XY: 3453 AN XY: 727224

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00945

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.000843

Gnomad4 NFE exome AF: 0.00547

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00288 AC: 439 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00284 AC XY: 211 AN XY: 74406

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00457

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00444 Hom.: 4

Bravo AF: 0.00323

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00355 AC: 431

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00504

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 26, 2023	BS2, PM1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2023	- -

not specified Uncertain:1 Benign:2

Likely 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	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in one patient with spherocytosis (Van Zweiten 2013). MAF 0.5%. -

Autosomal dominant distal renal tubular acidosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary spherocytosis type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hemolytic anemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary spherocytosis type 4;C5436235:Renal tubular acidosis, distal, 4, with hemolytic anemia;CN280572:Autosomal dominant distal renal tubular acidosis Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	4.5
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.65	T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.57	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.29	N;.
REVEL	Uncertain	0.51
Sift	Benign	0.21	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.0	B;.
Vest4		0.17
MVP		0.98
MPC		0.43
ClinPred		0.00015	T
GERP RS		-2.0
Varity_R		0.11
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs147390654; hg19: chr17-42337247;