7-129189199-G-GCTC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_005631.5(SMO):c.50_51insCCT(p.Leu22dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000877 in 980,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: SMO NM_005631.5 inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.275

Genes affected

SMO (HGNC:11119): (smoothened, frizzled class receptor) The protein encoded by this gene is a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. The encoded protein tranduces signals to other proteins after activation by a hedgehog protein/patched protein complex. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000922 (77/835512) while in subpopulation SAS AF= 0.0013 (20/15370). AF 95% confidence interval is 0.000862. There are 0 homozygotes in gnomad4_exome. There are 47 alleles in male gnomad4_exome subpopulation. Median coverage is 15. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMO	NM_005631.5	c.50_51insCCT	p.Leu22dup	inframe_insertion	1/12	ENST00000249373.8
SMO	XM_047420759.1	c.-455_-454insCCT		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.50_51insCCT	p.Leu22dup	inframe_insertion	1/12	1	NM_005631.5	P1
SMO	ENST00000655644.1	c.50_51insCCT	p.Leu22dup	inframe_insertion, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.0000621 AC: 9 AN: 144978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000126

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000922 AC: 77 AN: 835512 Hom.: 0 Cov.: 15 AF XY: 0.000118 AC XY: 47 AN XY: 398792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.0000580

GnomAD4 genome AF: 0.0000621 AC: 9 AN: 144978 Hom.: 0 Cov.: 32 AF XY: 0.0000425 AC XY: 3 AN XY: 70668

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000126

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The SMO p.Leu23dup variant was identified in dbSNP (ID: rs936754227) but was not found in ClinVar, Cosmic, LOVD 3.0 or in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant was reported in the Genomics Evidence Neoplasia Information Exchange (GENIE) dataset in thyroid cancer, melanoma, glioma, leukemia, non-small cell lung cancer, cancer of unknown primary, endometrial cancer and breast cancer samples (Koyama_2019_PMID:30709382). This variant is an in-frame insertion resulting in the duplication of a leucine (leu) residue at codon 23; the impact of this alteration on SMO protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs936754227; hg19: chr7-128829040;