NM_000342.4:c.2311+364G>A

Variant names:

• chr17-44252754-C-T
• rs1476512
• NM_000342.4:c.2311+364G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000342.4(SLC4A1):​c.2311+364G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 152,124 control chromosomes in the GnomAD database, including 15,267 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (15267 hom., cov: 31)
• Consequence: SLC4A1 NM_000342.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.248
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 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.2311+364G>A		intron	N/A	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.2311+364G>A		intron	N/A	ENSP00000262418.6	P02730-1
	SLC4A1	ENST00000399246.3	TSL:5	c.1213+364G>A		intron	N/A	ENSP00000382190.3	A0A0A0MS98

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60821 AN: 152006 Hom.: 15269 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.425

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.400 AC: 60813 AN: 152124 Hom.: 15267 Cov.: 31 AF XY: 0.403 AC XY: 29967 AN XY: 74374

African (AFR) AF: 0.100 AC: 4161 AN: 41512

American (AMR) AF: 0.443 AC: 6765 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1443 AN: 3466

East Asian (EAS) AF: 0.214 AC: 1109 AN: 5182

South Asian (SAS) AF: 0.481 AC: 2318 AN: 4822

European-Finnish (FIN) AF: 0.615 AC: 6509 AN: 10576

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.542 AC: 36826 AN: 67972

Other (OTH) AF: 0.427 AC: 901 AN: 2112

Alfa AF: 0.461 Hom.: 27756

Bravo AF: 0.378

Asia WGS AF: 0.370 AC: 1286 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.4
DANN	Benign	0.62
PhyloP100		0.25
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: rs1476512; hg19: chr17-42330122;