rs121912757

Positions:

• chr17-44254616-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The ENST00000262418.12(SLC4A1):​c.1937G>A​(p.Arg646Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R646W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: SLC4A1 ENST00000262418.12 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:2
• Conservation: PhyloP100: 6.07

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 Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 17-44254616-C-T is Benign according to our data. Variant chr17-44254616-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17782.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=5, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.1937G>A	p.Arg646Gln	missense_variant	16/20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.1847G>A	p.Arg616Gln	missense_variant	15/19		XP_011523431.1
SLC4A1	XM_005257593.6	c.1742G>A	p.Arg581Gln	missense_variant	14/18		XP_005257650.1
SLC4A1	XM_011525130.2	c.1937G>A	p.Arg646Gln	missense_variant	16/18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.1937G>A	p.Arg646Gln	missense_variant	16/20	1	NM_000342.4	ENSP00000262418	P1
SLC4A1	ENST00000399246.3	c.839G>A	p.Arg280Gln	missense_variant	11/15	5		ENSP00000382190

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251134 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461840 Hom.: 0 Cov.: 35 AF XY: 0.0000234 AC XY: 17 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74322

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 14, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 07, 2020	- -

SWANN BLOOD GROUP ANTIGEN Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 23, 2019

- -

Hereditary spherocytosis type 4 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hemolytic anemia 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal dominant distal renal tubular acidosis 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.43
MVP		0.92
MPC		1.2
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.92

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: rs121912757; hg19: chr17-42331984;