11-533874-T-C

Variant names:

• chr11-533874-T-C
• rs121913233
• NM_005343.4:c.182A>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_005343.4(HRAS):​c.182A>G​(p.Gln61Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.88
• Publications: 433 publications found

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]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_005343.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-533875-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 11-533874-T-C is Pathogenic according to our data. Variant chr11-533874-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 160364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.182A>G	p.Gln61Arg	missense_variant	Exon 3 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.182A>G	p.Gln61Arg	missense_variant	Exon 3 of 6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.182A>G	p.Gln61Arg	missense_variant	Exon 3 of 6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.182A>G	p.Gln61Arg	missense_variant	Exon 3 of 6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Linear nevus sebaceous syndrome Pathogenic:1

Jan 15, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Vascular Tumors Including Pyogenic Granuloma Pathogenic:1

Feb 19, 2015

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 05, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in POC with non-immune hydrops fetalis in published literature (PMID: 35397126); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 25883647, 27635947, 24224811, 29493581, 32434131, 35397126) -

Salivary gland neoplasm Pathogenic:1

-

Department of Medical Oncology, City of Hope

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PM5_Supporting+PS2_Supporting+PS4_Supporting -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Jun 25, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	.;D;.;D;D
Eigen	Benign	0.10
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.4	M;M;M;M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.027	D;D;D;D;D
Sift4G	Uncertain	0.036	D;D;D;D;D
Polyphen		0.051	B;B;B;B;B
Vest4		0.90
MutPred		0.77		Loss of glycosylation at T58 (P = 0.1023);Loss of glycosylation at T58 (P = 0.1023);Loss of glycosylation at T58 (P = 0.1023);Loss of glycosylation at T58 (P = 0.1023);Loss of glycosylation at T58 (P = 0.1023);
MVP		0.93
MPC		1.1
ClinPred		0.96	D
GERP RS		3.6
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.94
Mutation Taster		=21/79	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913233; hg19: chr11-533874; COSMIC: COSV54236691; COSMIC: COSV54236691;