17-44258042-ACGGCAGCCAGGACCTGGGGGCTGAATG-A

Position:

• chr17-44258042-ACGGCAGCCAGGACCTGGGGGCTGAATG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM4 PP3 PP5_Very_Strong

The ENST00000262418.12(SLC4A1):​c.1199_1225del​(p.Ala400_Ala408del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SLC4A1 ENST00000262418.12 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 B:1
• Conservation: PhyloP100: 9.96

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 11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000262418.12.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-44258042-ACGGCAGCCAGGACCTGGGGGCTGAATG-A is Pathogenic according to our data. Variant chr17-44258042-ACGGCAGCCAGGACCTGGGGGCTGAATG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17753.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.1199_1225del	p.Ala400_Ala408del	inframe_deletion	11/20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_005257593.6	c.1004_1030del	p.Ala335_Ala343del	inframe_deletion	9/18		XP_005257650.1
SLC4A1	XM_011525129.3	c.1199_1225del	p.Ala400_Ala408del	inframe_deletion	11/19		XP_011523431.1
SLC4A1	XM_011525130.2	c.1199_1225del	p.Ala400_Ala408del	inframe_deletion	11/18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.1199_1225del	p.Ala400_Ala408del	inframe_deletion	11/20	1	NM_000342.4	ENSP00000262418	P1
SLC4A1	ENST00000399246.3	c.777+1193_777+1219del		intron_variant		5		ENSP00000382190

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152006 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251416 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135892

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461872 Hom.: 0 AF XY: 0.0000124 AC XY: 9 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152006 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74238

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000416

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This variant, c.1199_1225del, results in the deletion of 9 amino acid(s) of the SLC4A1 protein (p.Ala400_Ala408del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769664228, gnomAD 0.02%). This variant has been observed in individual(s) with autosomal dominant ovalocytosis and/or autosomal recessive distal renal tubular acidosis (PMID: 1722314, 1737855, 7919393, 7949112, 14618420, 19229254, 24652967, 28188436, 31672324, 31959358; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17753). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC4A1 function (PMID: 7689982, 16107207). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 25, 2023	- -

Renal tubular acidosis, distal, 4, with hemolytic anemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017753). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000046, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 19, 2023	Criteria applied: PM5_STR,PM4,PM2_SUP -

Southeast Asian ovalocytosis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with SLC4A1-related disease. Spherocytosis type 4 (MIM#612653) is caused by variants with a loss of function mechanism. Cryohydrocytosis (MIM#185020), distal renal tubular acidosis (dRTA) (MIM#1179800), dRTA 4 with hemolytic anemia (MIM#611590) and SA type ovalocytosis (SAO) (MIM#166900) are caused by variants with either a loss of function, or dominant negative mechanism (PMID: 27058983). (I) 0108 - This gene is associated with both recessive and dominant disease. Most reports for this gene are for dominant disease, however, individuals biallelic for variants causing SAO have the more severe phenotype, dRTA with hemolytic anemia (OMIM, PMID: 17557941). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has moderate conservation. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated anion exchange transporter domain (UniProt, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many heterozygous individuals with SA type ovalocytosis, and is highly prevalent within South Asian populations (PMID: 30124986, PMID: 19229254, PMID: 7949112). Additionally, carriers of this variant have some resistance to all forms of malaria (PMID: 31364155, OMIM). It is highly likely to be lethal in homozygosity, where rare survivors demonstrate severe anaemia, hydrops and distal renal tubular acidosis (PMID: 24652967). (SP) 1102 - Strong phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

BLOOD GROUP--DIEGO SYSTEM;C1832168:BLOOD GROUP--FROESE;C1832169:BLOOD GROUP--SWANN SYSTEM;C1861453:Cryohydrocytosis;C1862190:BLOOD GROUP--WRIGHT ANTIGEN;C1862191:BLOOD GROUP--WALDNER TYPE;C1862322:Southeast Asian ovalocytosis;C1970028:Malaria, susceptibility to;C2675212:Hereditary spherocytosis type 4;C5436235:Renal tubular acidosis, distal, 4, with hemolytic anemia;CN280572:Autosomal dominant distal renal tubular acidosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 27, 2022

- -

Distal renal tubular acidosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Oct 22, 2019

- -

Malaria, cerebral, resistance to Benign:1

protective, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs769664228; hg19: chr17-42335410;