rs774513767

Variant names:

• chr17-44249221-G-A
• rs774513767
• NM_000342.4:c.*1237C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000342.4(SLC4A1):​c.*1237C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 449,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: SLC4A1 NM_000342.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.667
• Publications: 0 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: Orphanet, G2P, 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
• cryohydrocytosis

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-44249221-G-A is Benign according to our data. Variant chr17-44249221-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 323485.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000448 (68/151700) while in subpopulation AMR AF = 0.00184 (28/15212). AF 95% confidence interval is 0.00131. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000342.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A1	NM_000342.4	MANE Select	c.*1237C>T		3_prime_UTR	Exon 20 of 20	NP_000333.1	P02730-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A1	ENST00000262418.12	TSL:1 MANE Select	c.*1237C>T		3_prime_UTR	Exon 20 of 20	ENSP00000262418.6	P02730-1
	SLC4A1	ENST00000399246.3	TSL:5	c.*1237C>T		3_prime_UTR	Exon 15 of 15	ENSP00000382190.3	A0A0A0MS98

Frequencies

GnomAD3 genomes AF: 0.000448 AC: 68 AN: 151700 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000806 AC: 100 AN: 124006 AF XY: 0.000855

Gnomad AFR exome AF: 0.000169

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00673

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.00308

GnomAD4 exome AF: 0.000520 AC: 155 AN: 298170 Hom.: 1 Cov.: 0 AF XY: 0.000517 AC XY: 88 AN XY: 170140

African (AFR) AF: 0.000122 AC: 1 AN: 8204

American (AMR) AF: 0.000932 AC: 24 AN: 25740

Ashkenazi Jewish (ASJ) AF: 0.00611 AC: 65 AN: 10632

East Asian (EAS) AF: 0.00 AC: 0 AN: 9026

South Asian (SAS) AF: 0.0000857 AC: 5 AN: 58376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12322

Middle Eastern (MID) AF: 0.000723 AC: 2 AN: 2766

European-Non Finnish (NFE) AF: 0.000299 AC: 47 AN: 157094

Other (OTH) AF: 0.000785 AC: 11 AN: 14010

GnomAD4 genome AF: 0.000448 AC: 68 AN: 151700 Hom.: 0 Cov.: 29 AF XY: 0.000473 AC XY: 35 AN XY: 74044

African (AFR) AF: 0.0000485 AC: 2 AN: 41222

American (AMR) AF: 0.00184 AC: 28 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000431

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant distal renal tubular acidosis (1)
-	-	1	Hemolytic anemia (1)
-	-	1	Hereditary spherocytosis type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.37
DANN	Benign	0.69
PhyloP100		-0.67

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: rs774513767; hg19: chr17-42326589; COSMIC: COSV52259561;