11-535777-G-T

Variant names:

• chr11-535777-G-T
• rs8176332
• NM_001441284.1:c.-161-3803G>T

Variant summary

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

The NM_001441284.1(LRRC56):​c.-161-3803G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 151,944 control chromosomes in the GnomAD database, including 2,087 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 0.14 (2087 hom., cov: 33)
• Consequence: LRRC56 NM_001441284.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.238
• Publications: 3 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: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• rhabdomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• 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=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441284.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC56	NM_001441284.1		c.-161-3803G>T		intron	N/A	NP_001428213.1
	LRRC56	NM_001441286.1		c.-161-3803G>T		intron	N/A	NP_001428215.1
	HRAS	NM_005343.4	MANE Select	c.-415C>A		upstream_gene	N/A	NP_005334.1	P01112-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000932528.1		c.-53-1402C>A		intron	N/A	ENSP00000602587.1
	HRAS	ENST00000932529.1		c.-54+1092C>A		intron	N/A	ENSP00000602588.1
	HRAS	ENST00000932530.1		c.-54+363C>A		intron	N/A	ENSP00000602589.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21307 AN: 151836 Hom.: 2084 Cov.: 33

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0790

Gnomad EAS AF: 0.0544

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.0942

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.140 AC: 21329 AN: 151944 Hom.: 2087 Cov.: 33 AF XY: 0.137 AC XY: 10152 AN XY: 74270

African (AFR) AF: 0.280 AC: 11599 AN: 41374

American (AMR) AF: 0.106 AC: 1625 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0790 AC: 274 AN: 3468

East Asian (EAS) AF: 0.0545 AC: 281 AN: 5152

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4826

European-Finnish (FIN) AF: 0.0610 AC: 646 AN: 10594

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.0942 AC: 6396 AN: 67926

Other (OTH) AF: 0.136 AC: 287 AN: 2112

Alfa AF: 0.0377 Hom.: 46

Bravo AF: 0.150

Asia WGS AF: 0.0560 AC: 194 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.7
DANN	Benign	0.49
PhyloP100		-0.24
PromoterAI		0.22	Neutral

Splicing

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

Other links and lift over

dbSNP: rs8176332; hg19: chr11-535777;