11-533911-C-T

Variant names:

• chr11-533911-C-T
• rs1277340795
• NM_005343.4:c.145G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005343.4(HRAS):​c.145G>A​(p.Glu49Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,718 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E49G) has been classified as Uncertain significance. The gene HRAS is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.92
• Publications: 9 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

Specifications for HRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.145G>A	p.Glu49Lys	missense	Exon 3 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.145G>A	p.Glu49Lys	missense	Exon 3 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.145G>A	p.Glu49Lys	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.145G>A	p.Glu49Lys	missense	Exon 3 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.145G>A	p.Glu49Lys	missense	Exon 3 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.145G>A		non_coding_transcript_exon	Exon 3 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460718 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726688

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: 26136

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52286

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Costello syndrome (1)
1	-	-	Vascular Tumors Including Pyogenic Granuloma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	-0.16	N
PhyloP100		5.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.028	D
Sift4G	Benign	0.17	T
Polyphen		0.47	P
Vest4		0.79
MutPred		0.49		Gain of methylation at E49 (P = 0.0466)
MVP		0.80
MPC		1.9
ClinPred		0.96	D
GERP RS		3.6
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.90
Mutation Taster		=5/95	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: rs1277340795; hg19: chr11-533911; COSMIC: COSV54243301;