17-44248849-GT-G

Variant names:

• chr17-44248849-GT-G
• rs57466226
• NM_000342.4:c.*1608delA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000342.4(SLC4A1):​c.*1608delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (10 hom., cov: 0)
  • Exomes 𝑓: 0.00091 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 10 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.*1608delA		3_prime_UTR_variant	Exon 20 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.*1608delA		3_prime_UTR_variant	Exon 19 of 19		XP_011523431.1
SLC4A1	XM_005257593.6	c.*1608delA		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.*1608delA		3_prime_UTR_variant	Exon 20 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.*1608delA		3_prime_UTR_variant	Exon 15 of 15	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 3644 AN: 60456 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.0809

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.0704

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0622

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000907 AC: 10 AN: 11020 Hom.: 0 Cov.: 0 AF XY: 0.00100 AC XY: 6 AN XY: 5990

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00113 AC: 2 AN: 1766

European-Finnish (FIN) AF: 0.00172 AC: 1 AN: 580

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

European-Non Finnish (NFE) AF: 0.000695 AC: 5 AN: 7194

Other (OTH) AF: 0.00377 AC: 2 AN: 530

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0603 AC: 3644 AN: 60460 Hom.: 10 Cov.: 0 AF XY: 0.0562 AC XY: 1509 AN XY: 26842

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0549 AC: 698 AN: 12708

American (AMR) AF: 0.0559 AC: 238 AN: 4258

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 159 AN: 1944

East Asian (EAS) AF: 0.0703 AC: 103 AN: 1466

South Asian (SAS) AF: 0.0173 AC: 29 AN: 1674

European-Finnish (FIN) AF: 0.0119 AC: 22 AN: 1856

Middle Eastern (MID) AF: 0.0769 AC: 6 AN: 78

European-Non Finnish (NFE) AF: 0.0653 AC: 2298 AN: 35172

Other (OTH) AF: 0.0618 AC: 47 AN: 760

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00977 Hom.: 73

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Distal Renal Tubular Acidosis, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spherocytosis, Dominant Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemolytic anemia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs57466226; hg19: chr17-42326217;