19-2717545-C-T

Position:

• chr19-2717545-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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]

ACMG classification

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/exons	MANE	Protein	UniProt
DIRAS1	NM_145173.4	c.262G>A	p.Val88Ile	missense_variant	2/2	ENST00000323469.5	NP_660156.1
DIRAS1	XM_047438274.1	c.364G>A	p.Val122Ile	missense_variant	3/3		XP_047294230.1
DIRAS1	XM_047438275.1	c.364G>A	p.Val122Ile	missense_variant	3/3		XP_047294231.1
DIRAS1	XM_047438276.1	c.364G>A	p.Val122Ile	missense_variant	3/3		XP_047294232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIRAS1	ENST00000323469.5	c.262G>A	p.Val88Ile	missense_variant	2/2	1	NM_145173.4	ENSP00000325836.3
DIRAS1	ENST00000585334.1	c.262G>A	p.Val88Ile	missense_variant	1/1	6		ENSP00000468417.1
DIRAS1	ENST00000588128.1	c.262G>A	p.Val88Ile	missense_variant	3/3	4		ENSP00000466733.1

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

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

Other links and lift over

dbSNP: rs1913852235; hg19: chr19-2717543;