17-44248890-C-T

Variant names:

• chr17-44248890-C-T
• rs5033
• NM_000342.4:c.*1568G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

SLC4A1 Gene-Disease associations (from GenCC):

• autosomal dominant distal renal tubular acidosis

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary spherocytosis type 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal tubular acidosis, distal, 4, with hemolytic anemia

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• southeast Asian ovalocytosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cryohydrocytosis

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.*1568G>A		3_prime_UTR_variant	Exon 20 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.*1568G>A		3_prime_UTR_variant	Exon 19 of 19		XP_011523431.1
SLC4A1	XM_005257593.6	c.*1568G>A		3_prime_UTR_variant	Exon 18 of 18		XP_005257650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.*1568G>A		3_prime_UTR_variant	Exon 20 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.*1568G>A		3_prime_UTR_variant	Exon 15 of 15	5		ENSP00000382190.3

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

African (AFR) AF: 0.682 AC: 30 AN: 44

American (AMR) AF: 0.814 AC: 197 AN: 242

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 66 AN: 90

East Asian (EAS) AF: 0.545 AC: 36 AN: 66

South Asian (SAS) AF: 0.860 AC: 1431 AN: 1664

European-Finnish (FIN) AF: 0.858 AC: 417 AN: 486

Middle Eastern (MID) AF: 0.708 AC: 17 AN: 24

European-Non Finnish (NFE) AF: 0.837 AC: 4038 AN: 4824

Other (OTH) AF: 0.866 AC: 322 AN: 372

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

African (AFR) AF: 0.502 AC: 16310 AN: 32492

American (AMR) AF: 0.695 AC: 8214 AN: 11826

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 1955 AN: 3342

East Asian (EAS) AF: 0.355 AC: 1314 AN: 3700

South Asian (SAS) AF: 0.758 AC: 2988 AN: 3944

European-Finnish (FIN) AF: 0.786 AC: 5929 AN: 7542

Middle Eastern (MID) AF: 0.696 AC: 174 AN: 250

European-Non Finnish (NFE) AF: 0.701 AC: 45166 AN: 64392

Other (OTH) AF: 0.649 AC: 1152 AN: 1776

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hemolytic anemia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5033; hg19: chr17-42326258;