rs8176335

Positions:

• chr11-535596-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The ENST00000468682.2(HRAS):​c.-53-1221G>A 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 151,030 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.096 (844 hom., cov: 33)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: HRAS ENST00000468682.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.37

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-535596-C-T is Benign according to our data. Variant chr11-535596-C-T is described in ClinVar as [Benign]. Clinvar id is 1291288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.-234G>A		upstream_gene_variant		ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.-234G>A		upstream_gene_variant		ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.-234G>A		upstream_gene_variant		1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.-234G>A		upstream_gene_variant		5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14450 AN: 150914 Hom.: 839 Cov.: 33

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.0876

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0929

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0865

GnomAD4 exome AF: 0.100 AC: 1 AN: 10 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 1 AN XY: 6

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.125

GnomAD4 genome AF: 0.0957 AC: 14458 AN: 151020 Hom.: 844 Cov.: 33 AF XY: 0.0980 AC XY: 7231 AN XY: 73786

Gnomad4 AFR AF: 0.0494

Gnomad4 AMR AF: 0.0743

Gnomad4 ASJ AF: 0.0876

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0922

Alfa AF: 0.103 Hom.: 110

Bravo AF: 0.0883

Asia WGS AF: 0.153 AC: 523 AN: 3440

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	12
DANN	Uncertain	0.98

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8176335; hg19: chr11-535596;