Variant 19-2717374-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_145173.4(DIRAS1):c.433G>T(p.Ala145Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,608,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

DIRAS1
NM_145173.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79

Variant links:

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]

DIRAS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2820764).

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIRAS1	NM_145173.4 linkuse as main transcript	c.433G>T	p.Ala145Ser	missense_variant	2/2	ENST00000323469.5	NP_660156.1	O95057
DIRAS1	XM_047438274.1 linkuse as main transcript	c.535G>T	p.Ala179Ser	missense_variant	3/3		XP_047294230.1
DIRAS1	XM_047438275.1 linkuse as main transcript	c.535G>T	p.Ala179Ser	missense_variant	3/3		XP_047294231.1
DIRAS1	XM_047438276.1 linkuse as main transcript	c.535G>T	p.Ala179Ser	missense_variant	3/3		XP_047294232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DIRAS1	ENST00000323469.5 linkuse as main transcript	c.433G>T	p.Ala145Ser	missense_variant	2/2	1	NM_145173.4	ENSP00000325836.3	O95057
DIRAS1	ENST00000585334.1 linkuse as main transcript	c.433G>T	p.Ala145Ser	missense_variant	1/1	6		ENSP00000468417.1	O95057
DIRAS1	ENST00000588128.1 linkuse as main transcript	c.*25G>T		downstream_gene_variant		4		ENSP00000466733.1	K7EN06

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1456646

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724796

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.00

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000145

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000955

Bravo

AF:

0.000382

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2023

The c.433G>T (p.A145S) alteration is located in exon 2 (coding exon 1) of the DIRAS1 gene. This alteration results from a G to T substitution at nucleotide position 433, causing the alanine (A) at amino acid position 145 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.20

N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.050

N;.

REVEL

Uncertain

0.33

Sift

Benign

0.18

T;.

Sift4G

Benign

0.23

T;T

Polyphen

0.049

B;B

Vest4

0.28

MutPred

0.32

Gain of disorder (P = 0.0831);Gain of disorder (P = 0.0831);

MVP

0.73

MPC

1.1

ClinPred

0.84

GERP RS

4.2

Varity_R

0.34

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over