rs1355346296

Variant names:

• chr20-46709737-A-C
• rs1355346296
• NM_030777.4:c.1A>C

Your query was ambiguous. Multiple possible variants found:

• chr20-46709737-A-C
• chr20-46709737-A-G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_030777.4(SLC2A10):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC2A10 NM_030777.4 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.65
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 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-C is Pathogenic according to our data. Variant chr20-46709737-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3730294.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394556 Hom.: 0 Cov.: 30 AF XY: 0.00000291 AC XY: 2 AN XY: 687920

African (AFR) AF: 0.00 AC: 0 AN: 31078

American (AMR) AF: 0.00 AC: 0 AN: 35622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25046

East Asian (EAS) AF: 0.00 AC: 0 AN: 35492

South Asian (SAS) AF: 0.00 AC: 0 AN: 79010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4842

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077962

Other (OTH) AF: 0.00 AC: 0 AN: 57778

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arterial tortuosity syndrome Pathogenic:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SLC2A10 mRNA. The next in-frame methionine is located at codon 117. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with arterial tortuosity (PMID: 29323665). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.62	T
PhyloP100		2.6
PROVEAN	Benign	-0.91	N;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.0040	B;.
Vest4		0.81
MutPred		0.98		Loss of catalytic residue at G2 (P = 0.1393);Loss of catalytic residue at G2 (P = 0.1393);
MVP		0.75
ClinPred		0.98	D
GERP RS		2.7
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.43
Mutation Taster		=33/167	disease causing

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

Other links and lift over

dbSNP: rs1355346296; hg19: chr20-45338376;