chr19-2717266-G-C

Position:

• chr19-2717266-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145173.4(DIRAS1):​c.541C>G​(p.Arg181Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: DIRAS1 NM_145173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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=0.13250539).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIRAS1	NM_145173.4	c.541C>G	p.Arg181Gly	missense_variant	2/2	ENST00000323469.5	NP_660156.1
DIRAS1	XM_047438274.1	c.643C>G	p.Arg215Gly	missense_variant	3/3		XP_047294230.1
DIRAS1	XM_047438275.1	c.643C>G	p.Arg215Gly	missense_variant	3/3		XP_047294231.1
DIRAS1	XM_047438276.1	c.643C>G	p.Arg215Gly	missense_variant	3/3		XP_047294232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIRAS1	ENST00000323469.5	c.541C>G	p.Arg181Gly	missense_variant	2/2	1	NM_145173.4	ENSP00000325836.3
DIRAS1	ENST00000585334.1	c.541C>G	p.Arg181Gly	missense_variant	1/1	6		ENSP00000468417.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

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

Mar 12, 2024

The c.541C>G (p.R181G) alteration is located in exon 2 (coding exon 1) of the DIRAS1 gene. This alteration results from a C to G substitution at nucleotide position 541, causing the arginine (R) at amino acid position 181 to be replaced by a glycine (G). 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	0.15
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.26	T;T
Polyphen		0.049	B;B
Vest4		0.37
MutPred		0.35		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP		0.70
MPC		1.4
ClinPred		0.78	D
GERP RS		1.1
Varity_R		0.18
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2717264;