NM_000342.4:c.*1605_*1608dupAAAA

Variant names:

• chr17-44248849-G-GTTTT
• rs57466226
• NM_000342.4:c.*1605_*1608dupAAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000342.4(SLC4A1):​c.*1605_*1608dupAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.032 (487 hom., cov: 0)
  • Exomes 𝑓: 0.00082 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.697
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant distal renal tubular acidosis

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary spherocytosis type 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal tubular acidosis, distal, 4, with hemolytic anemia

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• southeast Asian ovalocytosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cryohydrocytosis

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000817 (9/11020) while in subpopulation SAS AF = 0.00283 (5/1766). AF 95% confidence interval is 0.00112. There are 4 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.*1605_*1608dupAAAA		3_prime_UTR_variant	Exon 20 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.*1605_*1608dupAAAA		3_prime_UTR_variant	Exon 19 of 19		XP_011523431.1
SLC4A1	XM_005257593.6	c.*1605_*1608dupAAAA		3_prime_UTR_variant	Exon 18 of 18		XP_005257650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.*1605_*1608dupAAAA		3_prime_UTR_variant	Exon 20 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.*1605_*1608dupAAAA		3_prime_UTR_variant	Exon 15 of 15	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 1962 AN: 60754 Hom.: 487 Cov.: 0

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.0331

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.0467

Gnomad SAS AF: 0.00594

Gnomad FIN AF: 0.00431

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0265

Gnomad OTH AF: 0.0317

GnomAD4 exome AF: 0.000817 AC: 9 AN: 11020 Hom.: 4 Cov.: 0 AF XY: 0.000835 AC XY: 5 AN XY: 5990

African (AFR) AF: 0.00 AC: 0 AN: 42

American (AMR) AF: 0.00 AC: 0 AN: 658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 164

East Asian (EAS) AF: 0.00 AC: 0 AN: 54

South Asian (SAS) AF: 0.00283 AC: 5 AN: 1766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.000556 AC: 4 AN: 7194

Other (OTH) AF: 0.00 AC: 0 AN: 530

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0323 AC: 1962 AN: 60760 Hom.: 487 Cov.: 0 AF XY: 0.0311 AC XY: 840 AN XY: 26972

African (AFR) AF: 0.0615 AC: 786 AN: 12778

American (AMR) AF: 0.0129 AC: 55 AN: 4276

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 54 AN: 1954

East Asian (EAS) AF: 0.0466 AC: 69 AN: 1480

South Asian (SAS) AF: 0.00597 AC: 10 AN: 1676

European-Finnish (FIN) AF: 0.00431 AC: 8 AN: 1858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 78

European-Non Finnish (NFE) AF: 0.0265 AC: 938 AN: 35356

Other (OTH) AF: 0.0316 AC: 24 AN: 760

Alfa AF: 0.00461 Hom.: 73

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs57466226; hg19: chr17-42326217;