rs56361140

Positions:

• chr17-44260441-G-A
• chr17-44260441-G-C
• chr17-44260441-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000342.4(SLC4A1):​c.448C>T​(p.Arg150*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,632 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC4A1 NM_000342.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.20

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44260441-G-A is Pathogenic according to our data. Variant chr17-44260441-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.448C>T	p.Arg150*	stop_gained	6/20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.448C>T	p.Arg150*	stop_gained	6/19		XP_011523431.1
SLC4A1	XM_005257593.6	c.253C>T	p.Arg85*	stop_gained	4/18		XP_005257650.1
SLC4A1	XM_011525130.2	c.448C>T	p.Arg150*	stop_gained	6/18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.448C>T	p.Arg150*	stop_gained	6/20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.448C>T	p.Arg150*	stop_gained	6/15	5		ENSP00000382190.3
SLC4A1	ENST00000471005.5	n.382C>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461632 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2023	The SLC4A1 c.448C>T; p.Arg150Ter variant (rs56361140), also known as the Lyon allele, is reported in the literature in three individuals affected with spherocytosis (Alloisio 1996, Eber 1996). This variant is also reported in ClinVar (Variation ID: 17762). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is predicted to induce an early termination codon and results in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro functional analyses confirm reduced mRNA and protein levels (Alloisio 1996). Based on available information, this variant is considered to be pathogenic. REFERENCES Alloisio N et al. Hereditary spherocytosis with band 3 deficiency. Association with a nonsense mutation of the band 3 gene (allele Lyon), and aggravation by a low-expression allele occurring in trans (allele Genas). Blood. 1996 Aug 1. PMID: 8704215 Eber SW et al. Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis. Nature genetics. 1996 Jun. PMID: 8640229 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17762). This premature translational stop signal has been observed in individual(s) with spherocytosis (PMID: 8640229, 8704215). This sequence change creates a premature translational stop signal (p.Arg150*) in the SLC4A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC4A1 are known to be pathogenic (PMID: 8943874, 10926824, 23255290). -

Hereditary spherocytosis type 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.90
GERP RS		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56361140; hg19: chr17-42337809;