chr17-44251206-G-A

Position:

• chr17-44251206-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000342.4(SLC4A1):​c.2608C>T​(p.Arg870Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC4A1 NM_000342.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.64

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-44251206-G-A is Pathogenic according to our data. Variant chr17-44251206-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.2608C>T	p.Arg870Trp	missense_variant	19/20	ENST00000262418.12
SLC4A1	XM_011525129.3	c.2518C>T	p.Arg840Trp	missense_variant	18/19
SLC4A1	XM_005257593.6	c.2413C>T	p.Arg805Trp	missense_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.2608C>T	p.Arg870Trp	missense_variant	19/20	1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.1510C>T	p.Arg504Trp	missense_variant	14/15	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461046 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726770

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 04, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 870 of the SLC4A1 protein (p.Arg870Trp). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC4A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17776). This variant is also known as Prague III. This missense change has been observed in individuals with autosomal dominant hereditary spherocytosis (PMID: 7530501, 23255290). This variant is not present in population databases (gnomAD no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 15, 2021	PS3, PM2, PP3, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 24, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 21, 2022	The SLC4A1 c.2608C>T; p.Arg870Trp variant (rs28931585), also known as band 3 Prague III, is reported in the literature in three individuals affected with spherocytosis (Andolfo 2021, Bracher 2001, Jarolim 1995). In vitro functional analyses demonstrate that the mutant protein is unable to incorporate into cell membranes (Quilty 2000). This variant is also reported in ClinVar (Variation ID: 17776). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 870 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.907). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Andolfo I et al. Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients. Genes (Basel). 2021 Jun 23. PMID: 34201899 Bracher NA et al. Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III. Br J Haematol. 2001 Jun. PMID: 11380459 Jarolim P et al. Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis. Blood. 1995 Feb 1. PMID: 7530501 Quilty JA et al. Trafficking and folding defects in hereditary spherocytosis mutants of the human red cell anion exchanger. Traffic. 2000 Dec. PMID: 11208088 -

Hereditary spherocytosis type 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.4	D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.90		Loss of methylation at R870 (P = 0.0262);.;
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.73
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs28931585; hg19: chr17-42328574; COSMIC: COSV52258447; COSMIC: COSV52258447;