rs35807245

Positions:

• chr17-44255703-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000342.4(SLC4A1):​c.1770G>A​(p.Lys590=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,614,060 control chromosomes in the GnomAD database, including 354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 32)
  • Exomes 𝑓: 0.019 (326 hom.)
• Consequence: SLC4A1 NM_000342.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.08

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-44255703-C-T is Benign according to our data. Variant chr17-44255703-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44255703-C-T is described in Lovd as [Benign]. Variant chr17-44255703-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0149 (2263/152236) while in subpopulation AMR AF= 0.02 (306/15294). AF 95% confidence interval is 0.019. There are 28 homozygotes in gnomad4. There are 1050 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.1770G>A	p.Lys590=	synonymous_variant	14/20	ENST00000262418.12
SLC4A1	XM_011525129.3	c.1770G>A	p.Lys590=	synonymous_variant	14/19
SLC4A1	XM_005257593.6	c.1575G>A	p.Lys525=	synonymous_variant	12/18
SLC4A1	XM_011525130.2	c.1770G>A	p.Lys590=	synonymous_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.1770G>A	p.Lys590=	synonymous_variant	14/20	1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.778-482G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2263 AN: 152118 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0161 AC: 4060 AN: 251460 Hom.: 51 AF XY: 0.0163 AC XY: 2218 AN XY: 135902

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.0544

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0188 AC: 27523 AN: 1461824 Hom.: 326 Cov.: 33 AF XY: 0.0183 AC XY: 13343 AN XY: 727212

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.0525

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00241

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0149 AC: 2263 AN: 152236 Hom.: 28 Cov.: 32 AF XY: 0.0141 AC XY: 1050 AN XY: 74418

Gnomad4 AFR AF: 0.00330

Gnomad4 AMR AF: 0.0200

Gnomad4 ASJ AF: 0.0473

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0218 Hom.: 56

Bravo AF: 0.0164

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0244

EpiControl AF: 0.0227

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2021	- -

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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Hereditary spherocytosis type 4 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. -

Hemolytic anemia 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.5
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35807245; hg19: chr17-42333071;