17-44248849-GT-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000342.4(SLC4A1):c.*1608del 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, single submitter U:3
• Conservation: PhyloP100: -0.697

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 Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.*1608del		3_prime_UTR_variant	20/20	ENST00000262418.12
SLC4A1	XM_005257593.6	c.*1608del		3_prime_UTR_variant	18/18
SLC4A1	XM_011525129.3	c.*1608del		3_prime_UTR_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.*1608del		3_prime_UTR_variant	20/20	1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.*1608del		3_prime_UTR_variant	15/15	5

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

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: 0.00113

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.000695

Gnomad4 OTH exome AF: 0.00377

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

Gnomad4 AFR AF: 0.0549

Gnomad4 AMR AF: 0.0559

Gnomad4 ASJ AF: 0.0818

Gnomad4 EAS AF: 0.0703

Gnomad4 SAS AF: 0.0173

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.0653

Gnomad4 OTH AF: 0.0618

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Distal Renal Tubular Acidosis, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hemolytic anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs57466226; hg19: chr17-42326217;