19-2717503-T-G

Position:

• chr19-2717503-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_145173.4(DIRAS1):​c.304A>C​(p.Lys102Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIRAS1 NM_145173.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.190

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16835266).
• BP6: Variant 19-2717503-T-G is Benign according to our data. Variant chr19-2717503-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3272128.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIRAS1	NM_145173.4	c.304A>C	p.Lys102Gln	missense_variant	2/2	ENST00000323469.5	NP_660156.1
DIRAS1	XM_047438274.1	c.406A>C	p.Lys136Gln	missense_variant	3/3		XP_047294230.1
DIRAS1	XM_047438275.1	c.406A>C	p.Lys136Gln	missense_variant	3/3		XP_047294231.1
DIRAS1	XM_047438276.1	c.406A>C	p.Lys136Gln	missense_variant	3/3		XP_047294232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIRAS1	ENST00000323469.5	c.304A>C	p.Lys102Gln	missense_variant	2/2	1	NM_145173.4	ENSP00000325836.3
DIRAS1	ENST00000585334.1	c.304A>C	p.Lys102Gln	missense_variant	1/1	6		ENSP00000468417.1
DIRAS1	ENST00000588128.1	c.304A>C	p.Lys102Gln	missense_variant	3/3	4		ENSP00000466733.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.9
DANN	Benign	0.93
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.60	N;N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.22	N;.;.
REVEL	Benign	0.16
Sift	Benign	0.090	T;.;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.054
MutPred		0.45		Loss of ubiquitination at K102 (P = 0.0155);Loss of ubiquitination at K102 (P = 0.0155);Loss of ubiquitination at K102 (P = 0.0155);
MVP		0.33
MPC		1.2
ClinPred		0.10	T
GERP RS		-1.6
Varity_R		0.21
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2717501;