1-68047002-C-G

Variant names:

• chr1-68047002-C-G
• rs776654083
• NM_004675.5:c.296G>C

Variant summary

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

The NM_004675.5(DIRAS3):​c.296G>C​(p.Arg99Pro) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R99L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIRAS3 NM_004675.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92

Genes affected

DIRAS3 (HGNC:687): (DIRAS family GTPase 3) This gene encodes a member of the ras superfamily. This gene is imprinted gene with monoallelic expression of the paternal allele which is associated with growth suppression. The encoded protein acts as a tumor suppressor whose function is abrogated in many ovarian and breast cancers. This protein may also play a role autophagy in certain cancer cells by regulating the autophagosome initiation complex. [provided by RefSeq, Nov 2015]

GNG12-AS1 (HGNC:43938): (GNG12, DIRAS3 and WLS antisense RNA 1)

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=0.13902116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIRAS3	NM_004675.5	c.296G>C	p.Arg99Pro	missense_variant	Exon 2 of 2	ENST00000646789.1	NP_004666.1
GNG12-AS1	NR_040077.1	n.266+12239C>G		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIRAS3	ENST00000646789.1	c.296G>C	p.Arg99Pro	missense_variant	Exon 2 of 2		NM_004675.5	ENSP00000495736.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	1.5
DANN	Benign	0.44
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.32	.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.075	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	5.5	N;.
REVEL	Uncertain	0.39
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0050	B;B
Vest4		0.081
MutPred		0.65		Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);
MVP		0.81
MPC		0.95
ClinPred		0.031	T
GERP RS		0.43
Varity_R		0.30
gMVP		0.89

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: rs776654083; hg19: chr1-68512685; COSMIC: COSV63970756; COSMIC: COSV63970756;