rs104894227

Variant names:

• chr11-533553-T-C
• rs104894227
• NM_005343.4:c.350A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-533553-T-C
• chr11-533553-T-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PS3_Moderate PS4_Moderate PS2 PP3

This summary comes from the ClinGen Evidence Repository: The c.350A>G variant in the HRAS gene is a missense variant predicted to cause substitution of lysine by arginine at amino acid 117 (p.Lys117Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.916, which is above the threshold of 0.7, evidence that correlates with impact to HRAS function (PP3). At least 4 independent occurrences of this variant have been detected in patients with a RASopathy, of which 3 were reported as confirmed de novo cases while 1 was an unconfirmed de novo occurrence (PS2_VeryStrong, PS4_Moderate; PMID:16443854, 17979197, 35595280, 32313153). In vitro functional assays showed that the variant increased RAS/MEK/ERK activation compared to wildtype (PS3_Moderate; PMID:17979197, 21850009). 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: PS2_VeryStrong, PS4_Moderate, PS3_Modertae, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256490/MONDO:0021060/046

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 4.14
• Publications: 46 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 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.350A>G	p.Lys117Arg	missense	Exon 4 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.350A>G	p.Lys117Arg	missense	Exon 4 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.350A>G	p.Lys117Arg	missense	Exon 4 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.350A>G	p.Lys117Arg	missense	Exon 4 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.350A>G	p.Lys117Arg	missense	Exon 4 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.350A>G		non_coding_transcript_exon	Exon 4 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Costello syndrome (3)
1	-	-	not provided (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.91		Loss of methylation at K117 (P = 0.0042)
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		-0.093	Neutral
Varity_R		0.96
gMVP		0.86
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs104894227; hg19: chr11-533553;