17-44262056-C-T

Variant names:

• chr17-44262056-C-T
• rs999716
• NM_000342.4:c.107-420G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000342.4(SLC4A1):​c.107-420G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,135,160 control chromosomes in the GnomAD database, including 137,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13407 hom., cov: 30)
  • Exomes 𝑓: 0.50 (124507 hom.)
• Consequence: SLC4A1 NM_000342.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.60
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant distal renal tubular acidosis

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary spherocytosis type 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal tubular acidosis, distal, 4, with hemolytic anemia

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• southeast Asian ovalocytosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cryohydrocytosis

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-44262056-C-T is Benign according to our data. Variant chr17-44262056-C-T is described in ClinVar as Benign. ClinVar VariationId is 1286790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.107-420G>A		intron_variant	Intron 3 of 19	ENST00000262418.12	NP_000333.1
SLC4A1	XM_005257593.6	c.-119G>A		5_prime_UTR_variant	Exon 1 of 18		XP_005257650.1
SLC4A1	XM_011525129.3	c.107-420G>A		intron_variant	Intron 3 of 18		XP_011523431.1
SLC4A1	XM_011525130.2	c.107-420G>A		intron_variant	Intron 3 of 17		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.107-420G>A		intron_variant	Intron 3 of 19	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000471005.5	n.11G>A		non_coding_transcript_exon_variant	Exon 1 of 4	3
SLC4A1	ENST00000399246.3	c.107-420G>A		intron_variant	Intron 3 of 14	5		ENSP00000382190.3
SLC4A1	ENST00000498270.1	n.388-420G>A		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57188 AN: 151620 Hom.: 13403 Cov.: 30

Gnomad AFR AF: 0.0979

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.404

GnomAD4 exome AF: 0.498 AC: 489807 AN: 983422 Hom.: 124507 Cov.: 31 AF XY: 0.499 AC XY: 232031 AN XY: 464888

African (AFR) AF: 0.0728 AC: 1514 AN: 20804

American (AMR) AF: 0.431 AC: 3790 AN: 8802

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 3659 AN: 8844

East Asian (EAS) AF: 0.239 AC: 2579 AN: 10794

South Asian (SAS) AF: 0.542 AC: 22913 AN: 42240

European-Finnish (FIN) AF: 0.549 AC: 3815 AN: 6948

Middle Eastern (MID) AF: 0.430 AC: 940 AN: 2184

European-Non Finnish (NFE) AF: 0.512 AC: 434148 AN: 847812

Other (OTH) AF: 0.470 AC: 16449 AN: 34994

GnomAD4 genome AF: 0.377 AC: 57189 AN: 151738 Hom.: 13407 Cov.: 30 AF XY: 0.383 AC XY: 28425 AN XY: 74124

African (AFR) AF: 0.0976 AC: 4044 AN: 41446

American (AMR) AF: 0.431 AC: 6566 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1419 AN: 3464

East Asian (EAS) AF: 0.237 AC: 1216 AN: 5126

South Asian (SAS) AF: 0.558 AC: 2685 AN: 4808

European-Finnish (FIN) AF: 0.569 AC: 5963 AN: 10486

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.496 AC: 33681 AN: 67860

Other (OTH) AF: 0.406 AC: 855 AN: 2106

Alfa AF: 0.278 Hom.: 2998

Bravo AF: 0.354

Asia WGS AF: 0.417 AC: 1449 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 25, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27767102) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	17
DANN	Benign	0.63
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs999716; hg19: chr17-42339424;