rs145994112

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000359271.4(SLC2A10):​c.848C>A​(p.Ala283Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,080 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A283G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

SLC2A10
ENST00000359271.4 missense

Scores

5
10
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 2.41
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC2A10NM_030777.4 linkuse as main transcriptc.848C>A p.Ala283Asp missense_variant 2/5 ENST00000359271.4 NP_110404.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC2A10ENST00000359271.4 linkuse as main transcriptc.848C>A p.Ala283Asp missense_variant 2/51 NM_030777.4 ENSP00000352216 P1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251130
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135762
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000353
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000575
AC:
84
AN:
1461846
Hom.:
0
Cov.:
33
AF XY:
0.0000495
AC XY:
36
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000728
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152234
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJul 17, 2024PM3_supporting -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxAug 10, 2022Reported in a female child with arterial tortuosity syndrome, atrial septal defect, inguinal hernia, and corneal thinning who also harbored an additional variant in the SLC2A10 gene (Hardin et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23142374, 28726533) -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2023The p.A283D variant (also known as c.848C>A), located in coding exon 2 of the SLC2A10 gene, results from a C to A substitution at nucleotide position 848. The alanine at codon 283 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration was reported as a compound heterozygote in a seven year old female with arterial tortuosity, atrial septal defect and corneal thinning (Hardin JS et al. Ophthalmic Genet, 2018 Jul;39:29-34). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Arterial tortuosity syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 22, 2022This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 283 of the SLC2A10 protein (p.Ala283Asp). This variant is present in population databases (rs145994112, gnomAD 0.008%). This missense change has been observed in individual(s) with arterial tortuosity syndrome (PMID: 28726533). ClinVar contains an entry for this variant (Variation ID: 213748). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC2A10 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.28
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Uncertain
0.32
Eigen_PC
Benign
0.15
FATHMM_MKL
Benign
0.38
N
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.033
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Uncertain
0.14
D
MutationAssessor
Pathogenic
3.7
H
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-2.5
N
REVEL
Uncertain
0.53
Sift
Uncertain
0.010
D
Sift4G
Uncertain
0.021
D
Polyphen
0.97
D
Vest4
0.86
MVP
0.90
MPC
0.35
ClinPred
0.96
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.94

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145994112; hg19: chr20-45354523; API