19-2717374-C-T

Variant names:

• chr19-2717374-C-T
• rs769610964
• NM_145173.4:c.433G>A

Variant summary

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

The NM_145173.4(DIRAS1):​c.433G>A​(p.Ala145Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A145S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DIRAS1 NM_145173.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.79

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIRAS1	NM_145173.4	c.433G>A	p.Ala145Thr	missense_variant	Exon 2 of 2	ENST00000323469.5	NP_660156.1
DIRAS1	XM_047438274.1	c.535G>A	p.Ala179Thr	missense_variant	Exon 3 of 3		XP_047294230.1
DIRAS1	XM_047438275.1	c.535G>A	p.Ala179Thr	missense_variant	Exon 3 of 3		XP_047294231.1
DIRAS1	XM_047438276.1	c.535G>A	p.Ala179Thr	missense_variant	Exon 3 of 3		XP_047294232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIRAS1	ENST00000323469.5	c.433G>A	p.Ala145Thr	missense_variant	Exon 2 of 2	1	NM_145173.4	ENSP00000325836.3
DIRAS1	ENST00000585334.1	c.433G>A	p.Ala145Thr	missense_variant	Exon 1 of 1	6		ENSP00000468417.1
DIRAS1	ENST00000588128.1	c.*25G>A		downstream_gene_variant		4		ENSP00000466733.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246828 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134166

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456646 Hom.: 0 Cov.: 34 AF XY: 0.00000552 AC XY: 4 AN XY: 724796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.86	L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.074	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.87	P;P
Vest4		0.60
MutPred		0.33		Gain of ubiquitination at K143 (P = 0.0898);Gain of ubiquitination at K143 (P = 0.0898);
MVP		0.71
MPC		1.6
ClinPred		0.86	D
GERP RS		4.2
Varity_R		0.42
gMVP		0.81

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: rs769610964; hg19: chr19-2717372;