rs1389642131

Variant names:

• chr19-2717776-C-T
• rs1389642131
• NM_145173.4:c.31G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145173.4(DIRAS1):​c.31G>A​(p.Val11Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,232 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DIRAS1 NM_145173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65
• Publications: 0 publications found

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]

ENSG00000267001 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145173.4. 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
	DIRAS1	NM_145173.4	MANE Select	c.31G>A	p.Val11Met	missense	Exon 2 of 2	NP_660156.1	O95057

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIRAS1	ENST00000323469.5	TSL:1 MANE Select	c.31G>A	p.Val11Met	missense	Exon 2 of 2	ENSP00000325836.3	O95057
	ENSG00000267001	ENST00000586572.1	TSL:4	c.310G>A	p.Val104Met	missense	Exon 3 of 3	ENSP00000467958.1	K7EQS6
	DIRAS1	ENST00000585334.1	TSL:6	c.31G>A	p.Val11Met	missense	Exon 1 of 1	ENSP00000468417.1	O95057

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000832 AC: 2 AN: 240344 AF XY: 0.00000762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000201

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 AF: 0.00000138 AC: 2 AN: 1449232 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 721370

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111740

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 33

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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.72		Gain of disorder (P = 0.1225)
MVP		0.85
MPC		2.3
ClinPred		0.93	D
GERP RS		3.9
PromoterAI		0.12	Neutral
Varity_R		0.73
gMVP		0.89
Mutation Taster		=26/74	disease causing

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: rs1389642131; hg19: chr19-2717774;