19-2717545-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145173.4(DIRAS1):​c.262G>A​(p.Val88Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DIRAS1
NM_145173.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88
Variant links:
Genes affected
DIRAS1 (HGNC:19127): (DIRAS family GTPase 1) DIRAS1 belongs to a distinct branch of the functionally diverse Ras (see HRAS; MIM 190020) superfamily of monomeric GTPases.[supplied by OMIM, Apr 2004]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12588072).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DIRAS1NM_145173.4 linkc.262G>A p.Val88Ile missense_variant Exon 2 of 2 ENST00000323469.5 NP_660156.1 O95057
DIRAS1XM_047438274.1 linkc.364G>A p.Val122Ile missense_variant Exon 3 of 3 XP_047294230.1
DIRAS1XM_047438275.1 linkc.364G>A p.Val122Ile missense_variant Exon 3 of 3 XP_047294231.1
DIRAS1XM_047438276.1 linkc.364G>A p.Val122Ile missense_variant Exon 3 of 3 XP_047294232.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DIRAS1ENST00000323469.5 linkc.262G>A p.Val88Ile missense_variant Exon 2 of 2 1 NM_145173.4 ENSP00000325836.3 O95057
DIRAS1ENST00000585334.1 linkc.262G>A p.Val88Ile missense_variant Exon 1 of 1 6 ENSP00000468417.1 O95057
DIRAS1ENST00000588128.1 linkc.262G>A p.Val88Ile missense_variant Exon 3 of 3 4 ENSP00000466733.1 K7EN06
ENSG00000267001ENST00000586572.1 linkc.*224G>A downstream_gene_variant 4 ENSP00000467958.1 K7EQS6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460852
Hom.:
0
Cov.:
34
AF XY:
0.00000275
AC XY:
2
AN XY:
726710
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 30, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.262G>A (p.V88I) alteration is located in exon 2 (coding exon 1) of the DIRAS1 gene. This alteration results from a G to A substitution at nucleotide position 262, causing the valine (V) at amino acid position 88 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
18
DANN
Benign
0.35
DEOGEN2
Benign
0.20
T;T;T
Eigen
Benign
-0.99
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.89
.;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.080
N;N;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.30
N;.;.
REVEL
Benign
0.14
Sift
Benign
1.0
T;.;.
Sift4G
Benign
1.0
T;T;T
Polyphen
0.19
B;B;.
Vest4
0.073
MutPred
0.56
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.32
MPC
0.91
ClinPred
0.25
T
GERP RS
1.8
Varity_R
0.035
gMVP
0.69

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: rs1913852235; hg19: chr19-2717543; API