rs121912748

Variant names:

• chr17-44253327-C-G
• rs121912748
• NM_000342.4:c.2102G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-44253327-C-G
• chr17-44253327-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000342.4(SLC4A1):​c.2102G>C​(p.Gly701Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G701D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC4A1 NM_000342.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• 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: 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000342.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44253327-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.2102G>C	p.Gly701Ala	missense_variant	Exon 17 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.2012G>C	p.Gly671Ala	missense_variant	Exon 16 of 19		XP_011523431.1
SLC4A1	XM_005257593.6	c.1907G>C	p.Gly636Ala	missense_variant	Exon 15 of 18		XP_005257650.1
SLC4A1	XM_011525130.2	c.2102G>C	p.Gly701Ala	missense_variant	Exon 17 of 18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.2102G>C	p.Gly701Ala	missense_variant	Exon 17 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.1004G>C	p.Gly335Ala	missense_variant	Exon 12 of 15	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.6	L;.
PhyloP100		7.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.98		Loss of glycosylation at S700 (P = 0.0391);.;
MVP		0.91
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.97

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: rs121912748; hg19: chr17-42330695;