rs5015

Variant names:

• chr17-44258019-G-A
• rs5015
• NM_000342.4:c.1249C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000342.4(SLC4A1):​c.1249C>T​(p.Leu417Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,614,124 control chromosomes in the GnomAD database, including 1,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (89 hom., cov: 31)
  • Exomes 𝑓: 0.042 (1454 hom.)
• Consequence: SLC4A1 NM_000342.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.00
• Publications: 10 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-44258019-G-A is Benign according to our data. Variant chr17-44258019-G-A is described in ClinVar as Benign. ClinVar VariationId is 255904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0306 (4656/152262) while in subpopulation NFE AF = 0.0433 (2944/68020). AF 95% confidence interval is 0.042. There are 89 homozygotes in GnomAd4. There are 2231 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 89 AD,AR,Unknown gene

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.1249C>T	p.Leu417Leu	synonymous	Exon 11 of 20	NP_000333.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A1	ENST00000262418.12	TSL:1 MANE Select	c.1249C>T	p.Leu417Leu	synonymous	Exon 11 of 20	ENSP00000262418.6
	SLC4A1	ENST00000399246.3	TSL:5	c.777+1243C>T		intron	N/A	ENSP00000382190.3

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4661 AN: 152144 Hom.: 89 Cov.: 31

Gnomad AFR AF: 0.00799

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.0519

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0364

GnomAD2 exomes AF: 0.0334 AC: 8404 AN: 251372 AF XY: 0.0350

Gnomad AFR exome AF: 0.00732

Gnomad AMR exome AF: 0.0240

Gnomad ASJ exome AF: 0.0351

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0508

Gnomad NFE exome AF: 0.0420

Gnomad OTH exome AF: 0.0362

GnomAD4 exome AF: 0.0418 AC: 61086 AN: 1461862 Hom.: 1454 Cov.: 33 AF XY: 0.0417 AC XY: 30326 AN XY: 727244

African (AFR) AF: 0.00672 AC: 225 AN: 33480

American (AMR) AF: 0.0251 AC: 1122 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0361 AC: 944 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0348 AC: 3006 AN: 86258

European-Finnish (FIN) AF: 0.0505 AC: 2699 AN: 53400

Middle Eastern (MID) AF: 0.0418 AC: 241 AN: 5768

European-Non Finnish (NFE) AF: 0.0454 AC: 50497 AN: 1112002

Other (OTH) AF: 0.0388 AC: 2342 AN: 60394

GnomAD4 genome AF: 0.0306 AC: 4656 AN: 152262 Hom.: 89 Cov.: 31 AF XY: 0.0300 AC XY: 2231 AN XY: 74440

African (AFR) AF: 0.00797 AC: 331 AN: 41550

American (AMR) AF: 0.0278 AC: 425 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 115 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4820

European-Finnish (FIN) AF: 0.0519 AC: 551 AN: 10612

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0433 AC: 2944 AN: 68020

Other (OTH) AF: 0.0361 AC: 76 AN: 2108

Alfa AF: 0.0362 Hom.: 255

Bravo AF: 0.0284

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0439

EpiControl AF: 0.0407

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	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	-0.46
CADD	Benign	3.5
DANN	Benign	0.69
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs5015; hg19: chr17-42335387;