20-46709737-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.65

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_030777.4 (SLC2A10) was described as [Pathogenic] in Lovd
• 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/exons	MANE	UniProt
SLC2A10	NM_030777.4	c.1A>G	p.Met1?	start_lost	1/5	ENST00000359271.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A10	ENST00000359271.4	c.1A>G	p.Met1?	start_lost	1/5	1	NM_030777.4	P1
SLC2A10	ENST00000486000.2	c.1A>G	p.Met1?	start_lost	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000144 AC: 2 AN: 138642 Hom.: 0 AF XY: 0.0000133 AC XY: 1 AN XY: 75202

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 SAS 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: 4 AN: 1394556 Hom.: 0 Cov.: 30 AF XY: 0.00000291 AC XY: 2 AN XY: 687920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000281

Gnomad4 ASJ exome AF: 0.0000399

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arterial tortuosity syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 2022	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D
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	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.92
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs1355346296; hg19: chr20-45338376;