11-533586-G-C

Variant names:

• chr11-533586-G-C
• rs730880462
• NM_005343.4:c.317C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005343.4(HRAS):​c.317C>G​(p.Ser106Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,534 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S106L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.70
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain GTPase HRas (size 185) in uniprot entity RASH_HUMAN there are 38 pathogenic changes around while only 16 benign (70%) in NM_005343.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.317C>G	p.Ser106Trp	missense_variant	Exon 4 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.317C>G	p.Ser106Trp	missense_variant	Exon 4 of 6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.317C>G	p.Ser106Trp	missense_variant	Exon 4 of 6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.317C>G	p.Ser106Trp	missense_variant	Exon 4 of 6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461534 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jul 29, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser106Trp (TCG>TGG): c.317 C>G in exon 4 of the HRAS gene (NM_005343.2). The S106W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Mutations in the HRAS gene are associated with Noonan spectrum disorders, including Costello syndrome. Noonan syndrome is a developmental disorder characterized by short stature, dysmorphic facial features, cardiac defects and developmental delay (Tartaglia M et al., 2002; Allanson J et al., 2011). In addition to features of Noonan syndrome, individuals with Costello syndrome typically have musculoskeletal abnormalities and tumor predisposition (Gripp K and Lin A, 2012). Hypertrophic cardiomyopathy (HCM) and arrhythmia have been reported in individuals with Costello syndrome, however the percentage of individuals with HCM and/or arrhythmia is currently unknown. The S106W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S106W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties and this substitution occurs at a position that is conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s). -

Costello syndrome Uncertain:1

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 106 of the HRAS protein (p.Ser106Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 180850). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HRAS protein 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. -

Cardiovascular phenotype Uncertain:1

Feb 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S106W variant (also known as c.317C>G), located in coding exon 3 of the HRAS gene, results from a C to G substitution at nucleotide position 317. The serine at codon 106 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;D;.;D;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Uncertain	0.024	D
MutationAssessor	Uncertain	2.6	M;M;M;M;M
PhyloP100		4.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.62
MutPred		0.34		Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);
MVP		0.92
MPC		2.4
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		-0.0069	Neutral
Varity_R		0.91
gMVP		0.74
Mutation Taster		=14/86	disease causing

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: rs730880462; hg19: chr11-533586;