11-533458-G-C

Position:

• chr11-533458-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005343.4(HRAS):​c.445C>G​(p.Arg149Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_005343.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRAS	NM_005343.4	c.445C>G	p.Arg149Gly	missense_variant	4/6	ENST00000311189.8
HRAS	NM_176795.5	c.445C>G	p.Arg149Gly	missense_variant	4/6	ENST00000417302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRAS	ENST00000311189.8	c.445C>G	p.Arg149Gly	missense_variant	4/6	1	NM_005343.4	P1
HRAS	ENST00000417302.7	c.445C>G	p.Arg149Gly	missense_variant	4/6	5	NM_176795.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.041
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.66	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.035	D;T;D;T;T
Polyphen		0.95	P;B;P;B;B
Vest4		0.57
MutPred		0.54		Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);Loss of solvent accessibility (P = 0.0044);
MVP		0.81
MPC		1.7
ClinPred		0.97	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.64

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-533458;