rs8176330

Variant names:

• chr11-535798-G-A
• rs8176330
• NM_001441284.1:c.-161-3782G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001441284.1(LRRC56):​c.-161-3782G>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 152,160 control chromosomes in the GnomAD database, including 958 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.096 (958 hom., cov: 33)
• Consequence: LRRC56 NM_001441284.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.269
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.-436C>T		upstream_gene_variant		ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.-436C>T		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.-436C>T		upstream_gene_variant		1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.-436C>T		upstream_gene_variant		5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14548 AN: 152052 Hom.: 955 Cov.: 33

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.0780

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.103

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

GnomAD4 genome AF: 0.0957 AC: 14555 AN: 152160 Hom.: 958 Cov.: 33 AF XY: 0.0934 AC XY: 6950 AN XY: 74374

African (AFR) AF: 0.0260 AC: 1080 AN: 41560

American (AMR) AF: 0.188 AC: 2870 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 351 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5168

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

European-Finnish (FIN) AF: 0.0780 AC: 827 AN: 10600

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.132 AC: 8940 AN: 67926

Other (OTH) AF: 0.102 AC: 215 AN: 2110

Alfa AF: 0.117 Hom.: 168

Bravo AF: 0.101

Asia WGS AF: 0.0310 AC: 106 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.6
DANN	Benign	0.76
PhyloP100		-0.27
PromoterAI		-0.037	Neutral

Splicing

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

Other links and lift over

dbSNP: rs8176330; hg19: chr11-535798;