11-533881-C-T

Variant names:

• chr11-533881-C-T
• rs727503093
• NM_005343.4:c.175G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PS4_Moderate PM1 PP1 PP3

This summary comes from the ClinGen Evidence Repository: The c.175G>A variant in the HRAS gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 59 (p.Ala59Thr). This variant was absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.755 supporting deleterious 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 c.175G>A (p.Ala59Thr) variant has been identified in at least 3 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners Laboratory for Molecular Medicine, Invitae internal data, ClinVar SCV000198374.4, SCV000950586.1). Moreover, this variant has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; Partners Laboratory for Molecular Medicine internal data, ClinVar SCV000198374.4). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM2_Supporting, PP1, PP3 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA176353/MONDO:0009026/046

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:2
• Conservation: PhyloP100: 7.77
• Publications: 38 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: Likely_pathogenic. The variant received 7 ACMG points.

• 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.
• PP1: 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.175G>A	p.Ala59Thr	missense	Exon 3 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.175G>A	p.Ala59Thr	missense	Exon 3 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.175G>A	p.Ala59Thr	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.175G>A	p.Ala59Thr	missense	Exon 3 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.175G>A	p.Ala59Thr	missense	Exon 3 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.175G>A		non_coding_transcript_exon	Exon 3 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000541 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Costello syndrome (3)
1	-	-	Non-small cell lung carcinoma (1)
-	1	-	not specified (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.040	D
Polyphen		0.81	P
Vest4		0.95
MutPred		0.78		Gain of glycosylation at T58 (P = 0.066)
MVP		0.96
MPC		1.4
ClinPred		0.99	D
GERP RS		3.6
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.93
gMVP		0.84
Mutation Taster		=13/87	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: rs727503093; hg19: chr11-533881; COSMIC: COSV54244375; COSMIC: COSV54244375;