17-44248849-G-GTTT

Position:

• chr17-44248849-G-GTTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000342.4(SLC4A1):​c.*1608_*1609insAAA 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 0.17 (2852 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (4 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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.*1608_*1609insAAA		3_prime_UTR_variant	20/20	ENST00000262418.12
SLC4A1	XM_005257593.6	c.*1608_*1609insAAA		3_prime_UTR_variant	18/18
SLC4A1	XM_011525129.3	c.*1608_*1609insAAA		3_prime_UTR_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.*1608_*1609insAAA		3_prime_UTR_variant	20/20	1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.*1608_*1609insAAA		3_prime_UTR_variant	15/15	5

Frequencies

GnomAD3 genomes AF: 0.170 AC: 10322 AN: 60762 Hom.: 2852 Cov.: 0

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0809

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.0695

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0238

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.00109 AC: 12 AN: 11020 Hom.: 4 Cov.: 0 AF XY: 0.000501 AC XY: 3 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: 0.000566

Gnomad4 FIN exome AF: 0.00345

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.170 AC: 10322 AN: 60768 Hom.: 2852 Cov.: 0 AF XY: 0.164 AC XY: 4434 AN XY: 26970

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.547

Gnomad4 SAS AF: 0.0698

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.161

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

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;