2-219629625-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005070.4(SLC4A3):c.541A>G(p.Arg181Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SLC4A3 NM_005070.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

Genes affected

SLC4A3 (HGNC:11029): (solute carrier family 4 member 3) The protein encoded by this gene is a plasma membrane anion exchange protein. The encoded protein has been found in brain, heart, kidney, small intestine, and lung. [provided by RefSeq, May 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC4A3
• BP4: Computational evidence support a benign effect (MetaRNN=0.12628987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A3	NM_005070.4	c.541A>G	p.Arg181Gly	missense_variant	5/23	ENST00000358055.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A3	ENST00000358055.8	c.541A>G	p.Arg181Gly	missense_variant	5/23	1	NM_005070.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

The c.541A>G (p.R181G) alteration is located in exon 5 (coding exon 4) of the SLC4A3 gene. This alteration results from a A to G substitution at nucleotide position 541, causing the arginine (R) at amino acid position 181 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.25	T;T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.20	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.97	N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.090	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.039	B;B;B;B
Vest4		0.20
MutPred		0.19		Loss of methylation at R181 (P = 0.0775);Loss of methylation at R181 (P = 0.0775);Loss of methylation at R181 (P = 0.0775);Loss of methylation at R181 (P = 0.0775);
MVP		0.63
ClinPred		0.13	T
GERP RS		3.3
Varity_R		0.090
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1698847121; hg19: chr2-220494347;