rs116640950

chr7-129212180-C-Gchr7-129212180-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_005631.5(SMO):c.2093C>G(p.Pro698Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,557,256 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.11

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074903667).
• BP6: Variant 7-129212180-C-G is Benign according to our data. Variant chr7-129212180-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 135260.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 = 0.00164 (250/152370) while in subpopulation NFE AF= 0.00294 (200/68028). AF 95% confidence interval is 0.00261. There are 1 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMO	NM_005631.5	c.2093C>G	p.Pro698Arg	missense_variant	12/12	ENST00000249373.8
SMO	XM_047420759.1	c.1703C>G	p.Pro568Arg	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.2093C>G	p.Pro698Arg	missense_variant	12/12	1	NM_005631.5	P1
	ENST00000466717.1	n.129+1237G>C		intron_variant, non_coding_transcript_variant		3
SMO	ENST00000655644.1	c.*1848C>G		3_prime_UTR_variant, NMD_transcript_variant	12/12
SMO	ENST00000475779.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152252 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00172 AC: 280 AN: 162392 Hom.: 1 AF XY: 0.00172 AC XY: 149 AN XY: 86540

Gnomad AFR exome AF: 0.000115

Gnomad AMR exome AF: 0.000912

Gnomad ASJ exome AF: 0.000234

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00122

Gnomad FIN exome AF: 0.000891

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00287

GnomAD4 exome AF: 0.00303 AC: 4255 AN: 1404886 Hom.: 9 Cov.: 32 AF XY: 0.00295 AC XY: 2047 AN XY: 693738

Gnomad4 AFR exome AF: 0.000472

Gnomad4 AMR exome AF: 0.000912

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000973

Gnomad4 FIN exome AF: 0.000952

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152370 Hom.: 1 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74514

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00236 Hom.: 1

Bravo AF: 0.00150

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000698 AC: 3

ESP6500EA AF: 0.00226 AC: 19

ExAC AF: 0.00134 AC: 156

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2019	This variant is associated with the following publications: (PMID: 24728327) -

SMO-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 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). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	14
Dann	Benign	0.81
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.15
Sift	Benign	0.31	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.053
MVP		0.71
MPC		0.070
ClinPred		0.0073	T
GERP RS		4.5
Varity_R		0.045
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs116640950; hg19: chr7-128852021; COSMIC: COSV99976457; COSMIC: COSV99976457;