4-71339318-T-A

Variant summary

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

The NM_003759.4(SLC4A4):c.70T>A(p.Phe24Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. F24C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SLC4A4 NM_003759.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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=0.028738767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A4	NM_003759.4	c.70T>A	p.Phe24Ile	missense_variant	1/23	ENST00000340595.4
SLC4A4	NM_001098484.3	c.254-52T>A		intron_variant		ENST00000264485.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A4	ENST00000340595.4	c.70T>A	p.Phe24Ile	missense_variant	1/23	1	NM_003759.4
SLC4A4	ENST00000264485.11	c.254-52T>A		intron_variant		1	NM_001098484.3	P3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251472 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135908

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 84 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74430

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive proximal renal tubular acidosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	10
Dann	Benign	0.87
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.11
Sift	Benign	0.64	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.0	B;B
Vest4		0.13
MVP		0.093
ClinPred		0.0085	T
GERP RS		4.2

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: rs200944017; hg19: chr4-72205035;