11-532700-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_005343.4(HRAS):​c.506G>A​(p.Arg169Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,613,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

HRAS
NM_005343.4 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.93
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 -5 ACMG points.

PM1
In a chain GTPase HRas, N-terminally processed (size 184) in uniprot entity RASH_HUMAN there are 63 pathogenic changes around while only 16 benign (80%) in NM_005343.4
BP4
Computational evidence support a benign effect (MetaRNN=0.15542921).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000657 (10/152250) while in subpopulation AFR AF= 0.000193 (8/41466). AF 95% confidence interval is 0.0000956. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HRASNM_005343.4 linkc.506G>A p.Arg169Gln missense_variant Exon 5 of 6 ENST00000311189.8 NP_005334.1 P01112-1X5D945
HRASNM_176795.5 linkc.*75G>A 3_prime_UTR_variant Exon 6 of 6 ENST00000417302.7 NP_789765.1 P01112-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HRASENST00000311189.8 linkc.506G>A p.Arg169Gln missense_variant Exon 5 of 6 1 NM_005343.4 ENSP00000309845.7 P01112-1
HRASENST00000417302 linkc.*75G>A 3_prime_UTR_variant Exon 6 of 6 5 NM_176795.5 ENSP00000388246.1 P01112-2

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000281
AC:
7
AN:
249282
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135174
show subpopulations
Gnomad AFR exome
AF:
0.000185
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:
0.0000357
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1460820
Hom.:
0
Cov.:
32
AF XY:
0.0000344
AC XY:
25
AN XY:
726736
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000450
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152250
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000276
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Costello syndrome Uncertain:2
Jul 31, 2019
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dec 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the HRAS protein (p.Arg169Gln). This variant is present in population databases (rs142218590, gnomAD 0.01%). This missense change has been observed in individual(s) with an unspecified cancer (PMID: 25742471). ClinVar contains an entry for this variant (Variation ID: 180856). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt HRAS function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1
Jun 05, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The R169Q variant has not been published in association with the Noonan syndrome spectrum to our knowledge; the variant has been observed as a germline variant in an individual with lung cancer but no reported other phenotype (Marks et al., 2007). It was observed to co-occur with the M269T pathogenic variant in the SOS1 gene in a patient at GeneDx. The variant is observed in 1/10172 (0.01%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). R169Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Hereditary cancer-predisposing syndrome Uncertain:1
Jan 10, 2022
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome Uncertain:1
May 09, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

HRAS-related disorder Uncertain:1
Feb 16, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HRAS c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-532700-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/180856/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
T;T;T
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.15
N;N;N
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.68
N;N;N
REVEL
Benign
0.22
Sift
Benign
0.13
T;T;T
Sift4G
Benign
0.95
T;T;T
Polyphen
0.0070
B;B;B
Vest4
0.26
MVP
0.70
MPC
1.1
ClinPred
0.072
T
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.5
Varity_R
0.26
gMVP
0.40

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.

Other links and lift over

dbSNP: rs142218590; hg19: chr11-532700; COSMIC: COSV99529522; COSMIC: COSV99529522; API