rs121917757

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PVS1_StrongBP6_ModerateBS2

The NM_005343.4(HRAS):​c.64C>T​(p.Gln22*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HRAS
NM_005343.4 stop_gained

Scores

5
1
1

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.94
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]
LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.888 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
BP6
Variant 11-534259-G-A is Benign according to our data. Variant chr11-534259-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 279996.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HRASNM_005343.4 linkuse as main transcriptc.64C>T p.Gln22* stop_gained 2/6 ENST00000311189.8 NP_005334.1 P01112-1X5D945
HRASNM_176795.5 linkuse as main transcriptc.64C>T p.Gln22* stop_gained 2/6 ENST00000417302.7 NP_789765.1 P01112-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HRASENST00000311189.8 linkuse as main transcriptc.64C>T p.Gln22* stop_gained 2/61 NM_005343.4 ENSP00000309845.7 P01112-1
HRASENST00000417302.7 linkuse as main transcriptc.64C>T p.Gln22* stop_gained 2/65 NM_176795.5 ENSP00000388246.1 P01112-2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250698
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135776
show subpopulations
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:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461360
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727016
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:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 30, 2019Predicted loss-of-function variant in a gene for which the disease mechanism is known to be gain-of-function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.62
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
1.0
D
Vest4
0.87
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs121917757; hg19: chr11-534259; COSMIC: COSV54249870; COSMIC: COSV54249870; API