rs121908856

Positions:

• chr4-71447706-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001098484.3(SLC4A4):​c.1026A>C​(p.Arg342Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC4A4 NM_001098484.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.34

Genes affected

SLC4A4 (HGNC:11030): (solute carrier family 4 member 4) This gene encodes a sodium bicarbonate cotransporter (NBC) involved in the regulation of bicarbonate secretion and absorption and intracellular pH. Mutations in this gene are associated with proximal renal tubular acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC4A4. . Gene score misZ 3.144 (greater than the threshold 3.09). Trascript score misZ 4.3739 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive proximal renal tubular acidosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 4-71447706-A-C is Pathogenic according to our data. Variant chr4-71447706-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 6471.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-71447706-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A4	NM_001098484.3	c.1026A>C	p.Arg342Ser	missense_variant	9/26	ENST00000264485.11	NP_001091954.1
SLC4A4	NM_003759.4	c.894A>C	p.Arg298Ser	missense_variant	6/23	ENST00000340595.4	NP_003750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A4	ENST00000264485.11	c.1026A>C	p.Arg342Ser	missense_variant	9/26	1	NM_001098484.3	ENSP00000264485	P3
SLC4A4	ENST00000340595.4	c.894A>C	p.Arg298Ser	missense_variant	6/23	1	NM_003759.4	ENSP00000344272

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive proximal renal tubular acidosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.7	.;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Uncertain	0.010	.;D;D;D;D;D
Polyphen		0.93	P;P;.;D;D;P
Vest4		0.99, 0.99, 0.99, 1.0
MutPred		0.96		Loss of methylation at R342 (P = 0.0273);Loss of methylation at R342 (P = 0.0273);Loss of methylation at R342 (P = 0.0273);Loss of methylation at R342 (P = 0.0273);.;.;
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908856; hg19: chr4-72313423;