11-536856-G-C

Variant names:

• chr11-536856-G-C
• rs7939028
• ENST00000462734.2:n.-574C>G

Variant summary

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

The ENST00000462734.2(HRAS):​n.-574C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 152,248 control chromosomes in the GnomAD database, including 5,015 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 0.24 (5015 hom., cov: 34)
  • Exomes 𝑓: 0.22 (0 hom.)
• Consequence: HRAS ENST00000462734.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.975
• Publications: 3 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC56	NM_001441284.1	c.-161-2724G>C		intron_variant	Intron 2 of 13		NP_001428213.1
LRRC56	NM_001441286.1	c.-161-2724G>C		intron_variant	Intron 2 of 12		NP_001428215.1
LRRC56	XM_011519875.3	c.-424-1742G>C		intron_variant	Intron 2 of 14		XP_011518177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000462734.2	n.-574C>G		non_coding_transcript_exon_variant	Exon 1 of 7	2		ENSP00000507303.1
HRAS	ENST00000468682.2	c.-57C>G		5_prime_UTR_variant	Exon 1 of 3	3		ENSP00000507989.1
HRAS	ENST00000462734.2	n.-574C>G		5_prime_UTR_variant	Exon 1 of 7	2		ENSP00000507303.1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37213 AN: 152114 Hom.: 5004 Cov.: 34

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.222 AC: 4 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.200 AC XY: 2 AN XY: 10

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: 0.500 AC: 1 AN: 2

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.188 AC: 3 AN: 16

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.245 AC: 37250 AN: 152230 Hom.: 5015 Cov.: 34 AF XY: 0.243 AC XY: 18081 AN XY: 74440

African (AFR) AF: 0.354 AC: 14692 AN: 41542

American (AMR) AF: 0.185 AC: 2834 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 580 AN: 3468

East Asian (EAS) AF: 0.185 AC: 960 AN: 5184

South Asian (SAS) AF: 0.216 AC: 1041 AN: 4826

European-Finnish (FIN) AF: 0.178 AC: 1893 AN: 10616

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.212 AC: 14440 AN: 67982

Other (OTH) AF: 0.235 AC: 497 AN: 2114

Alfa AF: 0.230 Hom.: 527

Bravo AF: 0.247

Asia WGS AF: 0.215 AC: 746 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.47
PhyloP100		-0.97
PromoterAI		-0.0078	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7939028; hg19: chr11-536856;