rs76315093

chr20-46726334-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030777.4(SLC2A10):c.1288+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,605,492 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (6 hom., cov: 33)
  • Exomes 𝑓: 0.014 (190 hom.)
• Consequence: SLC2A10 NM_030777.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-46726334-G-A is Benign according to our data. Variant chr20-46726334-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 139175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-46726334-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00892 (1359/152286) while in subpopulation SAS AF= 0.0154 (74/4816). AF 95% confidence interval is 0.0133. There are 6 homozygotes in gnomad4. There are 628 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A10	NM_030777.4	c.1288+10G>A		intron_variant		ENST00000359271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A10	ENST00000359271.4	c.1288+10G>A		intron_variant		1	NM_030777.4	P1

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 1359 AN: 152168 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0154

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.0103 AC: 2462 AN: 238094 Hom.: 25 AF XY: 0.0110 AC XY: 1433 AN XY: 129896

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.00557

Gnomad ASJ exome AF: 0.00896

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0158

Gnomad FIN exome AF: 0.00315

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0142 AC: 20567 AN: 1453206 Hom.: 190 Cov.: 33 AF XY: 0.0143 AC XY: 10350 AN XY: 723216

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.00857

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0168

Gnomad4 FIN exome AF: 0.00418

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00892 AC: 1359 AN: 152286 Hom.: 6 Cov.: 33 AF XY: 0.00843 AC XY: 628 AN XY: 74478

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0154

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0117 Hom.: 1

Bravo AF: 0.00900

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arterial tortuosity syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2020	Variant summary: SLC2A10 c.1288+10G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant strengthens a cryptic 3' acceptor site; two predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.01 in 238094 control chromosomes in the gnomAD database, including 25 homozygotes. The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC2A10 causing Aortopathy phenotype (0.0016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1288+10G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 12, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 30, 2015	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	14
Dann	Benign	0.59

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: rs76315093; hg19: chr20-45354973;