20-46709737-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5

The NM_030777.4(SLC2A10):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,394,556 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).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

SLC2A10
NM_030777.4 start_lost

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.65

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

arterial tortuosity syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SLC2A10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 117 codons. Genomic position: 46725385. Lost 0.215 part of the original CDS.

PS1

Another start lost variant in NM_030777.4 (SLC2A10) was described as [Likely_pathogenic] in ClinVar as 3319431

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-46709737-A-G is Pathogenic according to our data. Variant chr20-46709737-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2017181.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A10	NM_030777.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	ENST00000359271.4	NP_110404.1	O95528

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A10	ENST00000359271.4 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	1	NM_030777.4	ENSP00000352216.2		O95528
SLC2A10	ENST00000486000.2 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 2	3		ENSP00000478679.1		A0A087WUH5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000144

AC:

AN:

138642

AF XY:

0.0000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000412

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000207

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000287

AC:

AN:

1394556

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

687920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31078

American (AMR)

AF:

0.0000281

AC:

AN:

35622

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25046

East Asian (EAS)

AF:

0.00

AC:

AN:

35492

South Asian (SAS)

AF:

0.00

AC:

AN:

79010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4842

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077962

Other (OTH)

AF:

0.00

AC:

AN:

57778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arterial tortuosity syndrome

Pathogenic:1Uncertain:1

Jul 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SLC2A10 protein in which other variant(s) (p.Ser81Arg) have been determined to be pathogenic (PMID: 16550171, 18565096). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with SLC2A10-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the SLC2A10 mRNA. The next in-frame methionine is located at codon 117. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.90

D;.

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Benign

-0.62

PhyloP100

2.6

PROVEAN

Benign

-0.95

N;.

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.0030

B;.

Vest4

0.78

MutPred

0.99

Gain of catalytic residue at M1 (P = 0.0537);Gain of catalytic residue at M1 (P = 0.0537);

MVP

0.77

ClinPred

0.95

GERP RS

2.7

PromoterAI

-0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.92

gMVP

0.55

Mutation Taster

=33/167

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over