NM_000342.4:c.1323G>A

Variant names:

• chr17-44257767-C-T
• rs5017
• NM_000342.4:c.1323G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000342.4(SLC4A1):​c.1323G>A​(p.Leu441Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,902 control chromosomes in the GnomAD database, including 4,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L441L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.051 (286 hom., cov: 31)
  • Exomes 𝑓: 0.070 (4066 hom.)
• Consequence: SLC4A1 NM_000342.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.346
• Publications: 12 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, Labcorp Genetics (formerly Invitae), G2P
• cryohydrocytosis

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary spherocytosis type 4

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

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

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-44257767-C-T is Benign according to our data. Variant chr17-44257767-C-T is described in ClinVar as Benign. ClinVar VariationId is 255905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.346 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0799 is higher than 0.05.

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.1323G>A	p.Leu441Leu	synonymous	Exon 12 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.1323G>A	p.Leu441Leu	synonymous	Exon 12 of 20	ENSP00000262418.6	P02730-1
	SLC4A1	ENST00000399246.3	TSL:5	c.777+1495G>A		intron	N/A	ENSP00000382190.3	A0A0A0MS98

Frequencies

GnomAD3 genomes AF: 0.0509 AC: 7748 AN: 152128 Hom.: 286 Cov.: 31

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0395

Gnomad ASJ AF: 0.0920

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0410

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0523 AC: 13103 AN: 250552 AF XY: 0.0532

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.0966

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0405

Gnomad NFE exome AF: 0.0805

Gnomad OTH exome AF: 0.0622

GnomAD4 exome AF: 0.0698 AC: 101991 AN: 1461656 Hom.: 4066 Cov.: 34 AF XY: 0.0690 AC XY: 50161 AN XY: 727126

African (AFR) AF: 0.0120 AC: 401 AN: 33480

American (AMR) AF: 0.0310 AC: 1385 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0962 AC: 2515 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0197 AC: 1696 AN: 86250

European-Finnish (FIN) AF: 0.0444 AC: 2365 AN: 53300

Middle Eastern (MID) AF: 0.0687 AC: 395 AN: 5746

European-Non Finnish (NFE) AF: 0.0805 AC: 89502 AN: 1111934

Other (OTH) AF: 0.0617 AC: 3726 AN: 60386

GnomAD4 genome AF: 0.0509 AC: 7743 AN: 152246 Hom.: 286 Cov.: 31 AF XY: 0.0477 AC XY: 3553 AN XY: 74436

African (AFR) AF: 0.0137 AC: 569 AN: 41556

American (AMR) AF: 0.0393 AC: 602 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0920 AC: 319 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4814

European-Finnish (FIN) AF: 0.0410 AC: 435 AN: 10610

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0817 AC: 5554 AN: 68004

Other (OTH) AF: 0.0540 AC: 114 AN: 2112

Alfa AF: 0.0678 Hom.: 780

Bravo AF: 0.0489

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0856

EpiControl AF: 0.0848

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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	-0.44
CADD	Benign	5.2
DANN	Benign	0.61
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs5017; hg19: chr17-42335135; COSMIC: COSV108057608; COSMIC: COSV108057608;