Variant rs727504496 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_005343.4(HRAS):c.31G>C(p.Ala11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,898 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HRAS
NM_005343.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.28

Variant links:

Genes affected

HRAS (HGNC:5173): (HRas proto-oncogene, GTPase) This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]

HRAS links:

LRRC56 (HGNC:):

LRRC56 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a strand (size 8) in uniprot entity RASH_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_005343.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4 linkuse as main transcript	c.31G>C	p.Ala11Pro	missense_variant	2/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5 linkuse as main transcript	c.31G>C	p.Ala11Pro	missense_variant	2/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8 linkuse as main transcript	c.31G>C	p.Ala11Pro	missense_variant	2/6	1	NM_005343.4	ENSP00000309845	P1	P01112-1
HRAS	ENST00000417302.7 linkuse as main transcript	c.31G>C	p.Ala11Pro	missense_variant	2/6	5	NM_176795.5	ENSP00000388246		P01112-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460898

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726840

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.61

.;D;.;D;D

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.085

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.080

MetaRNN

Uncertain

0.73

D;D;D;D;D

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.98

L;L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.4

N;N;N;N;N

REVEL

Uncertain

0.48

Sift

Benign

0.13

T;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T

Polyphen

0.13

B;B;B;B;B

Vest4

0.73

MutPred

0.46

Gain of methylation at K16 (P = 0.0632);Gain of methylation at K16 (P = 0.0632);Gain of methylation at K16 (P = 0.0632);Gain of methylation at K16 (P = 0.0632);Gain of methylation at K16 (P = 0.0632);

MVP

0.88

MPC

1.5

ClinPred

0.81

GERP RS

3.0

Varity_R

0.86

gMVP

0.99

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over