17-44262056-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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	ENST00000399246.3	c.107-420G>A		intron_variant	Intron 3 of 14	5		ENSP00000382190.3
SLC4A1	ENST00000471005.5	n.11G>A		non_coding_transcript_exon_variant	Exon 1 of 4	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

Gnomad4 AFR exome AF: 0.0728

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.512

Gnomad4 OTH exome AF: 0.470

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

Gnomad4 AFR AF: 0.0976

Gnomad4 AMR AF: 0.431

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.558

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.496

Gnomad4 OTH AF: 0.406

Alfa AF: 0.279 Hom.: 918

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

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: rs999716; hg19: chr17-42339424;