11-533491-C-T

Variant names:

• chr11-533491-C-T
• rs397517142
• NM_005343.4:c.412G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

This summary comes from the ClinGen Evidence Repository: The c.412G>A (p.Gly138Ser) variant in the HRAS gene has been identified in 1 Asian woman with Noonan Syndrome and 1 Asian man with Costello Syndrome (Laboratory for Molecular Medicine internal data). It has been also identified in 1 patient who had a combined cardiac panel (GeneDx internal data) and was observed in 3 unrelated women with breast cancer and 1 woman with uterine cancer (Invitae internal data). PS4_Supporting not met due to conflicting phenotypes between the identified patients. HRAS has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, the clinical significance of the p.Gly138Ser variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA135988/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:7 B:2
• Conservation: PhyloP100: 2.68
• Publications: 3 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.412G>A	p.Gly138Ser	missense	Exon 4 of 6	NP_005334.1
	HRAS	NM_176795.5	MANE Plus Clinical	c.412G>A	p.Gly138Ser	missense	Exon 4 of 6	NP_789765.1
	HRAS	NM_001130442.3		c.412G>A	p.Gly138Ser	missense	Exon 4 of 5	NP_001123914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.412G>A	p.Gly138Ser	missense	Exon 4 of 6	ENSP00000309845.7
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.412G>A	p.Gly138Ser	missense	Exon 4 of 6	ENSP00000388246.1
	HRAS	ENST00000493230.5	TSL:1	n.412G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000434023.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251114 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461302 Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10 AN XY: 726976

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52902

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111958

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Costello syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	HRAS-related disorder (1)
-	1	-	Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome (1)
-	-	1	not specified (1)
-	1	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.21
Sift	Benign	0.042	D
Sift4G	Benign	0.079	T
Polyphen		0.68	P
Vest4		0.37
MVP		0.84
MPC		1.4
ClinPred		0.26	T
GERP RS		2.0
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.52
Mutation Taster		=22/78	disease causing

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: rs397517142; hg19: chr11-533491;