17-44248890-C-T

Position:

• chr17-44248890-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.*1568G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (27002 hom., cov: 17)
  • Exomes 𝑓: 0.84 (2751 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.58

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=-0.92).
• BP6: Variant 17-44248890-C-T is Benign according to our data. Variant chr17-44248890-C-T is described in ClinVar as [Benign]. Clinvar id is 323481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.*1568G>A		3_prime_UTR_variant	20/20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_005257593.6	c.*1568G>A		3_prime_UTR_variant	18/18		XP_005257650.1
SLC4A1	XM_011525129.3	c.*1568G>A		3_prime_UTR_variant	19/19		XP_011523431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.*1568G>A		3_prime_UTR_variant	20/20	1	NM_000342.4	ENSP00000262418	P1
SLC4A1	ENST00000399246.3	c.*1568G>A		3_prime_UTR_variant	15/15	5		ENSP00000382190

Frequencies

GnomAD3 genomes AF: 0.645 AC: 83849 AN: 130030 Hom.: 26982 Cov.: 17

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.648

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.839 AC: 6554 AN: 7812 Hom.: 2751 Cov.: 0 AF XY: 0.837 AC XY: 3801 AN XY: 4540

Gnomad4 AFR exome AF: 0.682

Gnomad4 AMR exome AF: 0.814

Gnomad4 ASJ exome AF: 0.733

Gnomad4 EAS exome AF: 0.545

Gnomad4 SAS exome AF: 0.860

Gnomad4 FIN exome AF: 0.858

Gnomad4 NFE exome AF: 0.837

Gnomad4 OTH exome AF: 0.866

GnomAD4 genome AF: 0.645 AC: 83921 AN: 130142 Hom.: 27002 Cov.: 17 AF XY: 0.649 AC XY: 40239 AN XY: 61984

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.695

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.355

Gnomad4 SAS AF: 0.758

Gnomad4 FIN AF: 0.786

Gnomad4 NFE AF: 0.701

Gnomad4 OTH AF: 0.649

Alfa AF: 0.637 Hom.: 3866

Bravo AF: 0.594

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.92
CADD	Benign	0.24
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: rs5033; hg19: chr17-42326258;