11-532452-C-G

Variant names:

• chr11-532452-C-G
• rs45565838
• NM_005343.4:c.*76G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005343.4(HRAS):​c.*76G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 834,816 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: HRAS NM_005343.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.201
• Publications: 1 publications found

Genes affected

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]

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]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289997 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 11-532452-C-G is Benign according to our data. Variant chr11-532452-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1182954.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00462 (703/152310) while in subpopulation AFR AF = 0.0163 (678/41570). AF 95% confidence interval is 0.0153. There are 6 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 703 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005343.4. 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
	HRAS	NM_005343.4	MANE Select	c.*76G>C		3_prime_UTR	Exon 6 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.*323G>C		3_prime_UTR	Exon 6 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.*184G>C		3_prime_UTR	Exon 5 of 5	NP_001123914.1	X5D945

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.*76G>C		3_prime_UTR	Exon 6 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.*323G>C		3_prime_UTR	Exon 6 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.*215G>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 704 AN: 152192 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000522 AC: 356 AN: 682506 Hom.: 0 Cov.: 9 AF XY: 0.000443 AC XY: 155 AN XY: 349844

African (AFR) AF: 0.0176 AC: 309 AN: 17600

American (AMR) AF: 0.000343 AC: 9 AN: 26236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16414

East Asian (EAS) AF: 0.00 AC: 0 AN: 32256

South Asian (SAS) AF: 0.00 AC: 0 AN: 53856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30116

Middle Eastern (MID) AF: 0.000405 AC: 1 AN: 2472

European-Non Finnish (NFE) AF: 0.0000192 AC: 9 AN: 469546

Other (OTH) AF: 0.000823 AC: 28 AN: 34010

GnomAD4 genome AF: 0.00462 AC: 703 AN: 152310 Hom.: 6 Cov.: 33 AF XY: 0.00448 AC XY: 334 AN XY: 74476

African (AFR) AF: 0.0163 AC: 678 AN: 41570

American (AMR) AF: 0.00124 AC: 19 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000418 Hom.: 0

Bravo AF: 0.00481

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.2
DANN	Benign	0.80
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs45565838; hg19: chr11-532452;