chr19-2717686-C-T

Position:

• chr19-2717686-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_145173.4(DIRAS1):​c.121G>A​(p.Glu41Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DIRAS1 NM_145173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIRAS1	NM_145173.4	c.121G>A	p.Glu41Lys	missense_variant	2/2	ENST00000323469.5	NP_660156.1
DIRAS1	XM_047438274.1	c.223G>A	p.Glu75Lys	missense_variant	3/3		XP_047294230.1
DIRAS1	XM_047438275.1	c.223G>A	p.Glu75Lys	missense_variant	3/3		XP_047294231.1
DIRAS1	XM_047438276.1	c.223G>A	p.Glu75Lys	missense_variant	3/3		XP_047294232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIRAS1	ENST00000323469.5	c.121G>A	p.Glu41Lys	missense_variant	2/2	1	NM_145173.4	ENSP00000325836.3
DIRAS1	ENST00000585334.1	c.121G>A	p.Glu41Lys	missense_variant	1/1	6		ENSP00000468417.1
DIRAS1	ENST00000588128.1	c.121G>A	p.Glu41Lys	missense_variant	3/3	4		ENSP00000466733.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459800 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726274

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.121G>A (p.E41K) alteration is located in exon 2 (coding exon 1) of the DIRAS1 gene. This alteration results from a G to A substitution at nucleotide position 121, causing the glutamic acid (E) at amino acid position 41 to be replaced by a lysine (K). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.7	M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D;.;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.87
MutPred		0.86		Gain of methylation at E41 (P = 0.0116);Gain of methylation at E41 (P = 0.0116);Gain of methylation at E41 (P = 0.0116);
MVP		0.80
MPC		2.4
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.93
gMVP		0.89

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: chr19-2717684;