rs376346077

chr20-46725431-G-Achr20-46725431-G-Cchr20-46725431-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_030777.4(SLC2A10):c.395G>A(p.Arg132Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SLC2A10
NM_030777.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 9.98

Variant links:

Genes affected

SLC2A10 (HGNC:13444): (solute carrier family 2 member 10) This gene encodes a member of the class III facilitative glucose transporter family. The encoded protein plays a role in regulation of glucose homeostasis. Mutations in this gene have been associated with arterial tortuosity syndrome.[provided by RefSeq, Dec 2009]

SLC2A10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 6) in uniprot entity GTR10_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_030777.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-46725431-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 535833.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

PP5

Variant 20-46725431-G-A is Pathogenic according to our data. Variant chr20-46725431-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1342029.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A10	NM_030777.4 linkuse as main transcript	c.395G>A	p.Arg132Gln	missense_variant	2/5	ENST00000359271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A10	ENST00000359271.4 linkuse as main transcript	c.395G>A	p.Arg132Gln	missense_variant	2/5	1	NM_030777.4	P1
SLC2A10	ENST00000611837.1 linkuse as main transcript	n.547G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251334

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000502

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arterial tortuosity syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 132 of the SLC2A10 protein (p.Arg132Gln). This variant is present in population databases (rs376346077, gnomAD 0.01%). This missense change has been observed in individual(s) with arterial tortuosity syndrome (PMID: 29323665). ClinVar contains an entry for this variant (Variation ID: 1342029). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC2A10 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg132 amino acid residue in SLC2A10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17935213, 28726533, 29543232). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 29, 2023

Variant summary: SLC2A10 c.395G>A (p.Arg132Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251334 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC2A10 causing Aortopathy (6e-05 vs 0.0016), allowing no conclusion about variant significance. c.395G>A has been reported in the literature in individuals affected with arterial tortuosity syndrome (Beyens_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29323665, 30090112). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2022

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30090112) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.41

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MVP

0.95

MPC

0.42

ClinPred

0.99

GERP RS

5.3

Varity_R

0.94

gMVP

0.80

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