rs147491841

chr7-129203570-G-Achr7-129203570-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005631.5(SMO):c.518G>A(p.Arg173His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,601,494 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (10 hom.)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.20

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075823963).
• BP6: Variant 7-129203570-G-A is Benign according to our data. Variant chr7-129203570-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000624 (95/152298) while in subpopulation SAS AF= 0.00622 (30/4822). AF 95% confidence interval is 0.00448. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMO	NM_005631.5	c.518G>A	p.Arg173His	missense_variant	2/12	ENST00000249373.8
SMO	XM_047420759.1	c.128G>A	p.Arg43His	missense_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.518G>A	p.Arg173His	missense_variant	2/12	1	NM_005631.5	P1
SMO	ENST00000655644.1	c.*382G>A		3_prime_UTR_variant, NMD_transcript_variant	3/12

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00108 AC: 255 AN: 236284 Hom.: 3 AF XY: 0.00126 AC XY: 162 AN XY: 128840

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.000614

Gnomad ASJ exome AF: 0.000809

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00405

Gnomad FIN exome AF: 0.0000745

Gnomad NFE exome AF: 0.000834

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.000728 AC: 1055 AN: 1449196 Hom.: 10 Cov.: 32 AF XY: 0.000853 AC XY: 615 AN XY: 721072

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000628

Gnomad4 ASJ exome AF: 0.000652

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00394

Gnomad4 FIN exome AF: 0.0000236

Gnomad4 NFE exome AF: 0.000445

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74458

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00106 Hom.: 3

Bravo AF: 0.000601

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00113 AC: 137

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.000952

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SMO-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 13, 2020

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 provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

SMO: BP4, BS2 -

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	0.077
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Benign	0.62
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.74	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.12
Sift	Benign	0.55	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.62
MPC		0.76
ClinPred		0.014	T
GERP RS		3.2
Varity_R		0.037
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs147491841; hg19: chr7-128843411; COSMIC: COSV50824204; COSMIC: COSV50824204;