7-129189198-G-GGCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005631.5(SMO):c.67_69dup(p.Leu23dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,146,950 control chromosomes in the GnomAD database, including 303 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (55 hom., cov: 32)
  • Exomes 𝑓: 0.023 (248 hom.)
• Consequence: SMO NM_005631.5 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.23

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 7-129189198-G-GGCT is Benign according to our data. Variant chr7-129189198-G-GGCT is described in ClinVar as [Likely_benign]. Clinvar id is 769335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0201 (3038/151452) while in subpopulation NFE AF= 0.0296 (2004/67736). AF 95% confidence interval is 0.0285. There are 55 homozygotes in gnomad4. There are 1535 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 55 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMO	NM_005631.5	c.67_69dup	p.Leu23dup	inframe_insertion	1/12	ENST00000249373.8
SMO	XM_047420759.1	c.-438_-436dup		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.67_69dup	p.Leu23dup	inframe_insertion	1/12	1	NM_005631.5	P1
SMO	ENST00000655644.1	c.67_69dup	p.Leu23dup	inframe_insertion, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3038 AN: 151350 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00593

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0492

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0296

Gnomad OTH AF: 0.0154

GnomAD3 exomes AF: 0.0165 AC: 6 AN: 364 Hom.: 0 AF XY: 0.0143 AC XY: 3 AN XY: 210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0229 AC: 22797 AN: 995498 Hom.: 248 Cov.: 15 AF XY: 0.0231 AC XY: 10940 AN XY: 473586

Gnomad4 AFR exome AF: 0.00413

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.000482

Gnomad4 SAS exome AF: 0.00280

Gnomad4 FIN exome AF: 0.0481

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0201 AC: 3038 AN: 151452 Hom.: 55 Cov.: 32 AF XY: 0.0207 AC XY: 1535 AN XY: 74006

Gnomad4 AFR AF: 0.00593

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000970

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0492

Gnomad4 NFE AF: 0.0296

Gnomad4 OTH AF: 0.0153

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2019	This variant is associated with the following publications: (PMID: 30709382, 23349881, 23826113) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 09, 2019	- -

SMO-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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: rs570242755; hg19: chr7-128829039;