rs8176334

Variant names:

• chr11-535603-G-A
• rs8176334
• NM_001441284.1:c.-161-3977G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-535603-G-A
• chr11-535603-G-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.-161-3977G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0623 in 151,302 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.062 (349 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC56 NM_001441284.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.606
• 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=-0.31).
• BP6: Variant 11-535603-G-A is Benign according to our data. Variant chr11-535603-G-A is described in ClinVar as Benign. ClinVar VariationId is 1279995.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.-241C>T		upstream_gene_variant		ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.-241C>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.-241C>T		upstream_gene_variant		1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.-241C>T		upstream_gene_variant		5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes AF: 0.0624 AC: 9428 AN: 151194 Hom.: 350 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0474

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0481

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0916

Gnomad OTH AF: 0.0848

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 8 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

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: 0.00 AC: 0 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0623 AC: 9424 AN: 151302 Hom.: 349 Cov.: 33 AF XY: 0.0611 AC XY: 4519 AN XY: 73944

African (AFR) AF: 0.0165 AC: 682 AN: 41408

American (AMR) AF: 0.0709 AC: 1079 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 263 AN: 3454

East Asian (EAS) AF: 0.0482 AC: 247 AN: 5122

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4824

European-Finnish (FIN) AF: 0.0587 AC: 606 AN: 10326

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.0915 AC: 6190 AN: 67638

Other (OTH) AF: 0.0839 AC: 177 AN: 2110

Alfa AF: 0.0314 Hom.: 24

Bravo AF: 0.0604

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.97
PhyloP100		0.61
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: rs8176334; hg19: chr11-535603;