rs8176333

Variant names:

• chr11-535649-C-T
• rs8176333
• NM_001441284.1:c.-161-3931C>T

Variant summary

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

The NM_001441284.1(LRRC56):​c.-161-3931C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 151,876 control chromosomes in the GnomAD database, including 4,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4833 hom., cov: 33)
  • Exomes 𝑓: 0.29 (0 hom.)
• Consequence: LRRC56 NM_001441284.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0840
• Publications: 4 publications found

Genes affected

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]

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]

HRAS Gene-Disease associations (from GenCC):

• Costello syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• rhabdomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-535649-C-T is Benign according to our data. Variant chr11-535649-C-T is described in ClinVar as Benign. ClinVar VariationId is 1259531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.-287G>A		upstream_gene_variant		ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.-287G>A		upstream_gene_variant		ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.-287G>A		upstream_gene_variant		1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.-287G>A		upstream_gene_variant		5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36626 AN: 151744 Hom.: 4822 Cov.: 33

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.228

GnomAD4 exome AF: 0.292 AC: 7 AN: 24 Hom.: 0 AF XY: 0.350 AC XY: 7 AN XY: 20

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.273 AC: 6 AN: 22

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.241 AC: 36662 AN: 151852 Hom.: 4833 Cov.: 33 AF XY: 0.240 AC XY: 17810 AN XY: 74224

African (AFR) AF: 0.342 AC: 14166 AN: 41462

American (AMR) AF: 0.184 AC: 2814 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 580 AN: 3460

East Asian (EAS) AF: 0.186 AC: 957 AN: 5148

South Asian (SAS) AF: 0.216 AC: 1042 AN: 4828

European-Finnish (FIN) AF: 0.179 AC: 1877 AN: 10498

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.213 AC: 14423 AN: 67866

Other (OTH) AF: 0.232 AC: 489 AN: 2108

Alfa AF: 0.232 Hom.: 547

Bravo AF: 0.243

Asia WGS AF: 0.212 AC: 729 AN: 3448

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.94
PhyloP100		0.084
PromoterAI		0.19	Neutral

Splicing

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

Other links and lift over

dbSNP: rs8176333; hg19: chr11-535649; COSMIC: COSV54238366;