chr17-44249184-TC-T

Position:

• chr17-44249184-TC-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000342.4(SLC4A1):​c.*1273del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 455,372 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (1 hom., cov: 29)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.747

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.*1273del		3_prime_UTR_variant	20/20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_005257593.6	c.*1273del		3_prime_UTR_variant	18/18		XP_005257650.1
SLC4A1	XM_011525129.3	c.*1273del		3_prime_UTR_variant	19/19		XP_011523431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.*1273del		3_prime_UTR_variant	20/20	1	NM_000342.4	ENSP00000262418	P1
SLC4A1	ENST00000399246.3	c.*1273del		3_prime_UTR_variant	15/15	5		ENSP00000382190

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 151962 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000477 AC: 62 AN: 129928 Hom.: 1 AF XY: 0.000550 AC XY: 39 AN XY: 70956

Gnomad AFR exome AF: 0.000165

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000539

Gnomad FIN exome AF: 0.00464

Gnomad NFE exome AF: 0.000485

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000630 AC: 191 AN: 303292 Hom.: 1 Cov.: 0 AF XY: 0.000556 AC XY: 96 AN XY: 172752

Gnomad4 AFR exome AF: 0.000117

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000536

Gnomad4 FIN exome AF: 0.00461

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.000775

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152080 Hom.: 1 Cov.: 29 AF XY: 0.000498 AC XY: 37 AN XY: 74362

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000208

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Spherocytosis, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Distal Renal Tubular Acidosis, 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: rs768606768; hg19: chr17-42326552;