rs34295241

Positions:

• chr20-46725710-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_030777.4(SLC2A10):​c.674G>A​(p.Arg225His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000915 in 1,614,086 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign 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. R225C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (9 hom.)
• Consequence: SLC2A10 NM_030777.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.33

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009985566).
• BP6: Variant 20-46725710-G-A is Benign according to our data. Variant chr20-46725710-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241606.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=3, Uncertain_significance=1}. Variant chr20-46725710-G-A is described in Lovd as [Benign]. Variant chr20-46725710-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00303 (461/152308) while in subpopulation AFR AF= 0.00994 (413/41568). AF 95% confidence interval is 0.00914. There are 0 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A10	NM_030777.4	c.674G>A	p.Arg225His	missense_variant	2/5	ENST00000359271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A10	ENST00000359271.4	c.674G>A	p.Arg225His	missense_variant	2/5	1	NM_030777.4	P1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00147 AC: 369 AN: 250864 Hom.: 3 AF XY: 0.00164 AC XY: 222 AN XY: 135686

Gnomad AFR exome AF: 0.00888

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00673

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000695 AC: 1016 AN: 1461778 Hom.: 9 Cov.: 33 AF XY: 0.000839 AC XY: 610 AN XY: 727200

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00662

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00301 AC XY: 224 AN XY: 74462

Gnomad4 AFR AF: 0.00994

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000431 Hom.: 0

Bravo AF: 0.00299

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2015	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	Eurofins Ntd Llc (ga)	Aug 28, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	Variant summary: SLC2A10 c.674G>A (p.Arg225His) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 250864 control chromosomes, including 3 homozygotes, predominantly at a frequency of 0.0089 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC2A10 causing Arterial Tortuosity Syndrome phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.674G>A has been reported in the literature in at least one homozygous individual affected with Arterial Tortuosity Syndrome (e.g., Beyens_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Arterial Tortuosity Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29323665). ClinVar contains an entry for this variant (Variation ID: 241606). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2015	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 01, 2019	- -

Arterial tortuosity syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 25, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.46
MVP		0.77
MPC		0.40
ClinPred		0.020	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.41

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: rs34295241; hg19: chr20-45354349; COSMIC: COSV63713921; COSMIC: COSV63713921;