1-68047002-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004675.5(DIRAS3):​c.296G>A​(p.Arg99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/22 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
• Publications: 6 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004675.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIRAS3	NM_004675.5	MANE Select	c.296G>A	p.Arg99His	missense	Exon 2 of 2	NP_004666.1	O95661
	GNG12-AS1	NR_040077.1		n.266+12239C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIRAS3	ENST00000646789.1	MANE Select	c.296G>A	p.Arg99His	missense	Exon 2 of 2	ENSP00000495736.1	O95661
	DIRAS3	ENST00000370981.3	TSL:2	c.296G>A	p.Arg99His	missense	Exon 4 of 4	ENSP00000360020.1	O95661
	DIRAS3	ENST00000691269.1		c.296G>A	p.Arg99His	missense	Exon 2 of 2	ENSP00000509833.1	O95661

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251424 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.9
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.11
MutPred		0.63		Loss of MoRF binding (P = 0.0475)
MVP		0.94
MPC		1.7
ClinPred		0.73	D
GERP RS		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.58
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs776654083; hg19: chr1-68512685; COSMIC: COSV63970862; COSMIC: COSV63970862;