chr4-71339289-G-C

Position:

• chr4-71339289-G-C

Variant summary

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

The NM_003759.4(SLC4A4):​c.41G>C​(p.Gly14Ala) 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. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G14E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC4A4 NM_003759.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

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 Uncertain_significance. Variant got 1 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 4.3578 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive proximal renal tubular acidosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.093103796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A4	NM_003759.4	c.41G>C	p.Gly14Ala	missense_variant	1/23	ENST00000340595.4
SLC4A4	NM_001098484.3	c.254-81G>C		intron_variant		ENST00000264485.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A4	ENST00000340595.4	c.41G>C	p.Gly14Ala	missense_variant	1/23	1	NM_003759.4
SLC4A4	ENST00000264485.11	c.254-81G>C		intron_variant		1	NM_001098484.3	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Aug 21, 2023

The c.41G>C (p.G14A) alteration is located in exon 1 (coding exon 1) of the SLC4A4 gene. This alteration results from a G to C substitution at nucleotide position 41, causing the glycine (G) at amino acid position 14 to be replaced by an alanine (A). 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
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.76
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;N;N
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.084
Sift	Benign	0.14	T;T
Sift4G	Benign	0.099	T;T
Polyphen		0.0	B;B
Vest4		0.10
MutPred		0.24		Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);
MVP		0.068
ClinPred		0.088	T
GERP RS		1.8

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-72205006;