4-71255295-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001098484.3(SLC4A4):c.149G>C(p.Gly50Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,613,320 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: SLC4A4 NM_001098484.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC4A4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0113144815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A4	NM_001098484.3	c.149G>C	p.Gly50Ala	missense_variant	3/26	ENST00000264485.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A4	ENST00000264485.11	c.149G>C	p.Gly50Ala	missense_variant	3/26	1	NM_001098484.3	P3

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 151888 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000702

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00157 AC: 390 AN: 249120 Hom.: 0 AF XY: 0.00152 AC XY: 205 AN XY: 135138

Gnomad AFR exome AF: 0.000711

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000789

Gnomad NFE exome AF: 0.00289

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00268 AC: 3914 AN: 1461312 Hom.: 8 Cov.: 33 AF XY: 0.00256 AC XY: 1860 AN XY: 726968

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00327

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00176 AC: 267 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74312

Gnomad4 AFR AF: 0.000700

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000945

Gnomad4 NFE AF: 0.00296

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00241 Hom.: 1

Bravo AF: 0.00184

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000516 AC: 2

ESP6500EA AF: 0.00279 AC: 23

ExAC AF: 0.00157 AC: 190

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00267

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T;.;.;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	L;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
Polyphen		0.034	B;B;.;P;.;.
Vest4		0.26, 0.27, 0.28
MVP		0.41
MPC		0.60
ClinPred		0.042	T
GERP RS		5.7
Varity_R		0.25
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs41265669; hg19: chr4-72121012;