17-44248849-G-GT

Position:

• chr17-44248849-G-GT

Variant summary

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

The NM_000342.4(SLC4A1):​c.*1608_*1609insA 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 0.055 (939 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (6 hom.)
• 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 (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.*1608_*1609insA		3_prime_UTR_variant	20/20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_005257593.6	c.*1608_*1609insA		3_prime_UTR_variant	18/18		XP_005257650.1
SLC4A1	XM_011525129.3	c.*1608_*1609insA		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.*1608_*1609insA		3_prime_UTR_variant	20/20	1	NM_000342.4	ENSP00000262418	P1
SLC4A1	ENST00000399246.3	c.*1608_*1609insA		3_prime_UTR_variant	15/15	5		ENSP00000382190

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 3321 AN: 60616 Hom.: 939 Cov.: 0

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0239

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00947

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.0238

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.0317

GnomAD4 exome AF: 0.00118 AC: 13 AN: 11020 Hom.: 6 Cov.: 0 AF XY: 0.00134 AC XY: 8 AN XY: 5990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000973

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0548 AC: 3322 AN: 60622 Hom.: 939 Cov.: 0 AF XY: 0.0536 AC XY: 1442 AN XY: 26924

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.00946

Gnomad4 SAS AF: 0.0161

Gnomad4 FIN AF: 0.00538

Gnomad4 NFE AF: 0.0353

Gnomad4 OTH AF: 0.0329

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;