4-71255295-G-A

Variant names:

• chr4-71255295-G-A
• rs41265669
• NM_001098484.3:c.149G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001098484.3(SLC4A4):​c.149G>A​(p.Gly50Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G50A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC4A4 NM_001098484.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35
• Publications: 6 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098484.3. 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_001098484.3	MANE Select	c.149G>A	p.Gly50Glu	missense	Exon 3 of 26	NP_001091954.1	Q9Y6R1-1
	SLC4A4	NM_001440629.1		c.242G>A	p.Gly81Glu	missense	Exon 3 of 26	NP_001427558.1
	SLC4A4	NM_001134742.2		c.149G>A	p.Gly50Glu	missense	Exon 3 of 25	NP_001128214.1	A5JJ20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A4	ENST00000264485.11	TSL:1 MANE Select	c.149G>A	p.Gly50Glu	missense	Exon 3 of 26	ENSP00000264485.5	Q9Y6R1-1
	SLC4A4	ENST00000351898.10	TSL:1	c.149G>A	p.Gly50Glu	missense	Exon 3 of 24	ENSP00000307349.7	Q9Y6R1-4
	SLC4A4	ENST00000514331.1	TSL:1	n.78G>A		non_coding_transcript_exon	Exon 1 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.59	N
PhyloP100		7.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.31
Sift	Benign	0.24	T
Sift4G	Uncertain	0.026	D
Polyphen		0.14	B
Vest4		0.38
MutPred		0.28		Gain of glycosylation at T49 (P = 0.0038)
MVP		0.21
MPC		0.74
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.41
gMVP		0.28
Mutation Taster		=73/27	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: rs41265669; hg19: chr4-72121012; COSMIC: COSV52634028;