rs145502796

Positions:

• chr17-44262740-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000342.4(SLC4A1):​c.16-14G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,072 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 32)
  • Exomes 𝑓: 0.019 (298 hom.)
• Consequence: SLC4A1 NM_000342.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.355

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=-0.82).
• BP6: Variant 17-44262740-C-T is Benign according to our data. Variant chr17-44262740-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44262740-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0135 (2062/152314) while in subpopulation NFE AF= 0.0201 (1370/68018). AF 95% confidence interval is 0.0193. There are 24 homozygotes in gnomad4. There are 1022 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.16-14G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262418.12
SLC4A1	XM_011525129.3	c.16-14G>A		splice_polypyrimidine_tract_variant, intron_variant
SLC4A1	XM_011525130.2	c.16-14G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.16-14G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.16-14G>A		splice_polypyrimidine_tract_variant, intron_variant		5
SLC4A1	ENST00000498270.1	n.283G>A		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2062 AN: 152196 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00412

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0136 AC: 3410 AN: 251380 Hom.: 38 AF XY: 0.0140 AC XY: 1901 AN XY: 135880

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.00879

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0192 AC: 27975 AN: 1460758 Hom.: 298 Cov.: 31 AF XY: 0.0190 AC XY: 13808 AN XY: 726758

Gnomad4 AFR exome AF: 0.00350

Gnomad4 AMR exome AF: 0.00906

Gnomad4 ASJ exome AF: 0.00517

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0143

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0219

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0135 AC: 2062 AN: 152314 Hom.: 24 Cov.: 32 AF XY: 0.0137 AC XY: 1022 AN XY: 74478

Gnomad4 AFR AF: 0.00411

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0123 Hom.: 2

Bravo AF: 0.0127

Asia WGS AF: 0.00404 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SLC4A1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2020	This variant is associated with the following publications: (PMID: 27884173, 23255290) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2023	- -

Autosomal dominant distal renal tubular acidosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hereditary spherocytosis type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Hemolytic anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.38

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: rs145502796; hg19: chr17-42340108;