Variant 22-32218707-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014227.3(SLC5A4):c.1787G>A(p.Arg596His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,608 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SLC5A4
NM_014227.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.508

Variant links:

Genes affected

SLC5A4 (HGNC:11039): (solute carrier family 5 member 4) Predicted to enable glucose:sodium symporter activity and proton transmembrane transporter activity. Predicted to be involved in sodium ion transport. Predicted to act upstream of or within proton transmembrane transport. Predicted to be active in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC5A4 links:

SLC5A4-AS1 (HGNC:):

SLC5A4-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016364038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC5A4	NM_014227.3 linkuse as main transcript	c.1787G>A	p.Arg596His	missense_variant	15/15	ENST00000266086.6	NP_055042.1	Q9NY91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC5A4	ENST00000266086.6 linkuse as main transcript	c.1787G>A	p.Arg596His	missense_variant	15/15	1	NM_014227.3	ENSP00000266086.3	Q9NY91
SLC5A4-AS1	ENST00000434942.2 linkuse as main transcript	n.225-10383C>T		intron_variant		3
SLC5A4-AS1	ENST00000452181.2 linkuse as main transcript	n.274+11431C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251248

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461450

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000655

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.1787G>A (p.R596H) alteration is located in exon 15 (coding exon 15) of the SLC5A4 gene. This alteration results from a G to A substitution at nucleotide position 1787, causing the arginine (R) at amino acid position 596 to be replaced by a histidine (H). 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

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.0078

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.60

M_CAP

Benign

0.012

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.68

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.4

REVEL

Benign

0.25

Sift

Benign

0.18

Sift4G

Benign

0.39

Polyphen

0.0080

Vest4

0.14

MVP

0.42

MPC

0.20

ClinPred

0.040

GERP RS

-0.46

Varity_R

0.023

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over