chr4-71339289-G-C

Variant names:

• chr4-71339289-G-C
• rs775702694
• NM_003759.4:c.41G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 15/18 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
• Publications: 0 publications found

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]

SLC4A4 Gene-Disease associations (from GenCC):

• autosomal recessive proximal renal tubular acidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.093103796).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003759.4. 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
	SLC4A4	NM_003759.4	MANE Plus Clinical	c.41G>C	p.Gly14Ala	missense	Exon 1 of 23	NP_003750.1	Q9Y6R1-2
	SLC4A4	NM_001098484.3	MANE Select	c.254-81G>C		intron	N/A	NP_001091954.1	Q9Y6R1-1
	SLC4A4	NM_001440629.1		c.347-81G>C		intron	N/A	NP_001427558.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A4	ENST00000340595.4	TSL:1 MANE Plus Clinical	c.41G>C	p.Gly14Ala	missense	Exon 1 of 23	ENSP00000344272.3	Q9Y6R1-2
	SLC4A4	ENST00000512686.5	TSL:1	c.41G>C	p.Gly14Ala	missense	Exon 1 of 11	ENSP00000422400.1	Q9Y6R1-3
	SLC4A4	ENST00000264485.11	TSL:1 MANE Select	c.254-81G>C		intron	N/A	ENSP00000264485.5	Q9Y6R1-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
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
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.87	T
PhyloP100		1.5
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.084
Sift	Benign	0.14	T
Sift4G	Benign	0.099	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.24		Gain of helix (P = 0.0225)
MVP		0.068
ClinPred		0.088	T
GERP RS		1.8
PromoterAI		0.048	Neutral
Mutation Taster		=87/13	polymorphism

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: rs775702694; hg19: chr4-72205006;