Variant 22-32221016-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014227.3(SLC5A4):c.1672C>T(p.Arg558Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000317 in 1,610,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R558H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SLC5A4
NM_014227.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.97

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC5A4	NM_014227.3 linkuse as main transcript	c.1672C>T	p.Arg558Cys	missense_variant	14/15	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.1672C>T	p.Arg558Cys	missense_variant	14/15	1	NM_014227.3	ENSP00000266086.3	Q9NY91
SLC5A4-AS1	ENST00000434942.2 linkuse as main transcript	n.225-8074G>A		intron_variant		3
SLC5A4-AS1	ENST00000452181.2 linkuse as main transcript	n.274+13740G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251298

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1458824

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

725938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000595

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000546

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

Sep 10, 2024

The c.1672C>T (p.R558C) alteration is located in exon 14 (coding exon 14) of the SLC5A4 gene. This alteration results from a C to T substitution at nucleotide position 1672, causing the arginine (R) at amino acid position 558 to be replaced by a cysteine (C). 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

0.24

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Benign

0.18

Eigen_PC

Benign

0.0079

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.5

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-7.1

REVEL

Uncertain

0.57

Sift

Uncertain

0.010

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.80

MVP

0.75

MPC

0.75

ClinPred

0.84

GERP RS

2.4

Varity_R

0.42

gMVP

0.52

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

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