NM_004675.5:c.547A>G

Variant names:

• chr1-68046751-T-C
• NM_004675.5:c.547A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004675.5(DIRAS3):​c.547A>G​(p.Lys183Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DIRAS3 NM_004675.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.45
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

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.547A>G	p.Lys183Glu	missense	Exon 2 of 2	NP_004666.1	O95661
	GNG12-AS1	NR_040077.1		n.266+11988T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIRAS3	ENST00000646789.1	MANE Select	c.547A>G	p.Lys183Glu	missense	Exon 2 of 2	ENSP00000495736.1	O95661
	DIRAS3	ENST00000370981.3	TSL:2	c.547A>G	p.Lys183Glu	missense	Exon 4 of 4	ENSP00000360020.1	O95661
	DIRAS3	ENST00000691269.1		c.547A>G	p.Lys183Glu	missense	Exon 2 of 2	ENSP00000509833.1	O95661

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.085	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.77		Loss of ubiquitination at K183 (P = 0.021)
MVP		0.93
MPC		1.9
ClinPred		0.98	D
GERP RS		2.0
Varity_R		0.71
gMVP		0.50
Mutation Taster		=85/15	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

hg19: chr1-68512434; COSMIC: COSV63971295; COSMIC: COSV63971295;