rs35601764

Variant names:

• chr11-532923-A-C
• rs35601764
• NM_005343.4:c.451-168T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005343.4(HRAS):​c.451-168T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0957 in 152,244 control chromosomes in the GnomAD database, including 962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). The gene HRAS is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.096 (962 hom., cov: 33)
• Consequence: HRAS NM_005343.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.235
• Publications: 13 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-532923-A-C is Benign according to our data. Variant chr11-532923-A-C is described in ClinVar as Benign. ClinVar VariationId is 561388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

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.451-168T>G		intron	N/A	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.*20-168T>G		intron	N/A	NP_789765.1	P01112-2
	LRRC56	NM_001441284.1		c.-162+4586A>C		intron	N/A	NP_001428213.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.451-168T>G		intron	N/A	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.*20-168T>G		intron	N/A	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.*20-168T>G		intron	N/A	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14555 AN: 152126 Hom.: 959 Cov.: 33

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.0778

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.104

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0957 AC: 14563 AN: 152244 Hom.: 962 Cov.: 33 AF XY: 0.0933 AC XY: 6948 AN XY: 74434

African (AFR) AF: 0.0257 AC: 1069 AN: 41542

American (AMR) AF: 0.188 AC: 2875 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 351 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5184

South Asian (SAS) AF: 0.0369 AC: 178 AN: 4830

European-Finnish (FIN) AF: 0.0778 AC: 826 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8952 AN: 67982

Other (OTH) AF: 0.103 AC: 218 AN: 2112

Alfa AF: 0.120 Hom.: 1319

Bravo AF: 0.101

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.72
DANN	Benign	0.40
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs35601764; hg19: chr11-532923;