rs121917758

Variant names:

• chr11-533883-G-A
• rs121917758
• NM_005343.4:c.173C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-533883-G-A
• chr11-533883-G-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2_Supporting PS2 PS1 PS4_Moderate PM1 PP3 PP2

This summary comes from the ClinGen Evidence Repository: The c.173C>T variant in the HRAS gene is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 58 (p.Thr58Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.777, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function (PP3). This variant resides within a region (amino acids 57 – 64), of HRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicity of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1). At least 4 independent occurrences of this variant have been detected in patients with a RASopathy, of which 1 was reported as a de novo occurrence (PS2, PS4_Moderate; CeGaT Center for Human Genetics, ClinVar SCV003916655.13; PMIDs: 22488832, 18247425, 23321623, 26888048). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS1, PS2, PS4_Moderate, PM1, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA341206/MONDO:0021060/046

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.80
• Publications: 40 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.173C>T	p.Thr58Ile	missense	Exon 3 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.173C>T	p.Thr58Ile	missense	Exon 3 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.173C>T	p.Thr58Ile	missense	Exon 3 of 5	NP_001123914.1	X5D945

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.173C>T	p.Thr58Ile	missense	Exon 3 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.173C>T	p.Thr58Ile	missense	Exon 3 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.173C>T		non_coding_transcript_exon	Exon 3 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460978 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726812

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52586

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Costello syndrome (6)
1	-	-	HRAS-related disorder (1)
1	-	-	not provided (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Loss of glycosylation at T58 (P = 0.0515)
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		2.7
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121917758; hg19: chr11-533883; COSMIC: COSV54240842; COSMIC: COSV54240842;