rs2072081

Positions:

chr17-44250125-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000342.4(SLC4A1):c.*333C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 355,356 control chromosomes in the GnomAD database, including 21,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 11320 hom., cov: 32)

Exomes 𝑓: 0.30 ( 10569 hom. )

Consequence

SLC4A1
NM_000342.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.88

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 17-44250125-G-T is Benign according to our data. Variant chr17-44250125-G-T is described in ClinVar as [Benign]. Clinvar id is 323498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
SLC4A1	NM_000342.4 linkuse as main transcript	c.*333C>A	3_prime_UTR_variant	20/20	ENST00000262418.12
SLC4A1	XM_005257593.6 linkuse as main transcript	c.*333C>A	3_prime_UTR_variant	18/18
SLC4A1	XM_011525129.3 linkuse as main transcript	c.*333C>A	3_prime_UTR_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12 linkuse as main transcript	c.*333C>A		3_prime_UTR_variant	20/20	1	NM_000342.4	P1	P02730-1
SLC4A1	ENST00000399246.3 linkuse as main transcript	c.*333C>A		3_prime_UTR_variant	15/15	5

Frequencies

GnomAD3 genomes

AF:

0.361

AC:

54775

AN:

151880

Hom.:

11317

Cov.:

show subpopulations

Gnomad AFR

AF:

0.529

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.349

Gnomad ASJ

AF:

0.397

Gnomad EAS

AF:

0.696

Gnomad SAS

AF:

0.262

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.349

GnomAD4 exome

AF:

0.297

AC:

60499

AN:

203358

Hom.:

10569

Cov.:

AF XY:

0.294

AC XY:

31387

AN XY:

106800

show subpopulations

Gnomad4 AFR exome

AF:

0.536

Gnomad4 AMR exome

AF:

0.336

Gnomad4 ASJ exome

AF:

0.381

Gnomad4 EAS exome

AF:

0.685

Gnomad4 SAS exome

AF:

0.243

Gnomad4 FIN exome

AF:

0.231

Gnomad4 NFE exome

AF:

0.258

Gnomad4 OTH exome

AF:

0.312

GnomAD4 genome

AF:

0.361

AC:

54811

AN:

151998

Hom.:

11320

Cov.:

AF XY:

0.360

AC XY:

26712

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.528

Gnomad4 AMR

AF:

0.350

Gnomad4 ASJ

AF:

0.397

Gnomad4 EAS

AF:

0.696

Gnomad4 SAS

AF:

0.261

Gnomad4 FIN

AF:

0.224

Gnomad4 NFE

AF:

0.265

Gnomad4 OTH

AF:

0.350

Alfa

AF:

0.285

Hom.:

13342

Bravo

AF:

0.380

Asia WGS

AF:

0.459

AC:

1595

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant distal renal tubular acidosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spherocytosis type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

- -

Hemolytic anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.033

DANN

Benign

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over