rs8176335

Variant names:

• chr11-535596-C-T
• rs8176335
• NM_001441284.1:c.-161-3984C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001441284.1(LRRC56):​c.-161-3984C>T 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: LRRC56 NM_001441284.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.37
• Publications: 2 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=-0.35).
• BP6: Variant 11-535596-C-T is Benign according to our data. Variant chr11-535596-C-T is described in ClinVar as Benign. ClinVar VariationId 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 rank	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 rank	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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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) AF: 0.00 AC: 0 AN: 2

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.125 AC: 1 AN: 8

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0494 AC: 2046 AN: 41400

American (AMR) AF: 0.0743 AC: 1129 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 303 AN: 3458

East Asian (EAS) AF: 0.131 AC: 670 AN: 5128

South Asian (SAS) AF: 0.185 AC: 893 AN: 4820

European-Finnish (FIN) AF: 0.117 AC: 1198 AN: 10226

Middle Eastern (MID) AF: 0.0828 AC: 24 AN: 290

European-Non Finnish (NFE) AF: 0.116 AC: 7800 AN: 67486

Other (OTH) AF: 0.0922 AC: 194 AN: 2104

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

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	-0.35
CADD	Benign	12
DANN	Uncertain	0.98
PhyloP100		-1.4
PromoterAI		0.069	Neutral

Splicing

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

Other links and lift over

dbSNP: rs8176335; hg19: chr11-535596;