rs139932041

chr20-46725967-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_030777.4(SLC2A10):c.931G>A(p.Val311Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,613,796 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: SLC2A10 NM_030777.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 2.84

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030691594).
• BP6: Variant 20-46725967-G-A is Benign according to our data. Variant chr20-46725967-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213720.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000235 (343/1461468) while in subpopulation MID AF= 0.00277 (16/5766). AF 95% confidence interval is 0.00174. There are 1 homozygotes in gnomad4_exome. There are 175 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A10	NM_030777.4	c.931G>A	p.Val311Ile	missense_variant	2/5	ENST00000359271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A10	ENST00000359271.4	c.931G>A	p.Val311Ile	missense_variant	2/5	1	NM_030777.4	P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000303 AC: 76 AN: 250954 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135702

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000235 AC: 343 AN: 1461468 Hom.: 1 Cov.: 33 AF XY: 0.000241 AC XY: 175 AN XY: 727048

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74478

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000246 Hom.: 1

Bravo AF: 0.000329

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arterial tortuosity syndrome Uncertain:2 Benign: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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2021	The SLC2A10 c.931G>A; p.Val311Ile variant (rs139932041), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 213720). This variant is found in the general population with an overall allele frequency of 0.029% (81/282,340 alleles) in the Genome Aggregation Database. The valine at codon 311 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.14). Due to limited information, the clinical significance of the p.Val311Ile variant is uncertain at this time. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2022	The c.931G>A (p.V311I) alteration is located in exon 2 (coding exon 2) of the SLC2A10 gene. This alteration results from a G to A substitution at nucleotide position 931, causing the valine (V) at amino acid position 311 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 05, 2018	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in patients with pulmonary arterial hypertension or with familial intracranial aneurysms (Abou Hassan et al., 2018; Song et al., 2022); This variant is associated with the following publications: (PMID: 34668355, 29843651) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.96	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.14
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
Polyphen		0.084	B
Vest4		0.19
MVP		0.61
MPC		0.20
ClinPred		0.010	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.17

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: rs139932041; hg19: chr20-45354606; COSMIC: COSV63714063; COSMIC: COSV63714063;