17-44253099-C-T

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.2311+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00639 in 1,606,888 control chromosomes in the GnomAD database, including 782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (673 hom.)
• Consequence: SLC4A1 NM_000342.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.62

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=-0.84).
• BP6: Variant 17-44253099-C-T is Benign according to our data. Variant chr17-44253099-C-T is described in ClinVar as [Benign]. Clinvar id is 255910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.2311+19G>A		intron_variant		ENST00000262418.12
SLC4A1	XM_005257593.6	c.2116+19G>A		intron_variant
SLC4A1	XM_011525129.3	c.2221+19G>A		intron_variant
SLC4A1	XM_011525130.2	c.2311+19G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.2311+19G>A		intron_variant		1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.1213+19G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00888 AC: 1351 AN: 152142 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.0159 AC: 3876 AN: 243402 Hom.: 363 AF XY: 0.0145 AC XY: 1917 AN XY: 132334

Gnomad AFR exome AF: 0.00424

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.00376

Gnomad FIN exome AF: 0.000178

Gnomad NFE exome AF: 0.000694

Gnomad OTH exome AF: 0.00659

GnomAD4 exome AF: 0.00613 AC: 8914 AN: 1454628 Hom.: 673 Cov.: 32 AF XY: 0.00606 AC XY: 4386 AN XY: 723832

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.174

Gnomad4 SAS exome AF: 0.00445

Gnomad4 FIN exome AF: 0.000216

Gnomad4 NFE exome AF: 0.000720

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00884 AC: 1346 AN: 152260 Hom.: 109 Cov.: 32 AF XY: 0.00954 AC XY: 710 AN XY: 74444

Gnomad4 AFR AF: 0.00491

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00334 Hom.: 7

Bravo AF: 0.00975

Asia WGS AF: 0.0570 AC: 198 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.13
Dann	Benign	0.56

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: rs2285643; hg19: chr17-42330467; COSMIC: COSV52262665; COSMIC: COSV52262665;