chr7-129203570-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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. 17/22 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

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 1.20

Publications

9 publications found

Variant links:

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]

SMO Gene-Disease associations (from GenCC):

Curry-Jones syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
congenital hypothalamic hamartoma syndrome
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, ClinGen
Hirschsprung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SMO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 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 VariationId is 135267.Status of the report is criteria_provided_single_submitter, 1 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMO	NM_005631.5 link	c.518G>A	p.Arg173His	missense_variant	Exon 2 of 12	ENST00000249373.8	NP_005622.1
SMO	XM_047420759.1 link	c.128G>A	p.Arg43His	missense_variant	Exon 3 of 13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SMO	ENST00000249373.8 link	c.518G>A	p.Arg173His	missense_variant	Exon 2 of 12	1	NM_005631.5	ENSP00000249373.3
SMO	ENST00000655644.1 link	n.*382G>A		non_coding_transcript_exon_variant	Exon 3 of 12			ENSP00000499377.1
SMO	ENST00000655644.1 link	n.*382G>A		3_prime_UTR_variant	Exon 3 of 12			ENSP00000499377.1

Frequencies

GnomAD3 genomes

AF:

0.000637

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00108

AC:

255

AN:

236284

AF XY:

0.00126

show subpopulations

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 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.:

Cov.:

AF XY:

0.000853

AC XY:

615

AN XY:

721072

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33452

American (AMR)

AF:

0.000628

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.000652

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00394

AC:

338

AN:

85698

European-Finnish (FIN)

AF:

0.0000236

AC:

AN:

42360

Middle Eastern (MID)

AF:

0.0193

AC:

111

AN:

5762

European-Non Finnish (NFE)

AF:

0.000445

AC:

494

AN:

1111342

Other (OTH)

AF:

0.00101

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

107

161

214

268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000624

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41564

American (AMR)

AF:

0.000588

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000601

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00113

AC:

137

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.000982

EpiControl

AF:

0.000952

ClinVar

Significance: Likely benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

SMO-related disorder

Benign:1

Oct 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMO: BP4, BS2 -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.34

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.66

M_CAP

Benign

0.048

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.2

PhyloP100

1.2

PrimateAI

Benign

0.25

PROVEAN

Benign

0.040

REVEL

Benign

0.12

Sift

Benign

0.55

Sift4G

Benign

0.88

Polyphen

0.0

Vest4

0.18

MVP

0.62

MPC

0.76

ClinPred

0.014

GERP RS

3.2

Varity_R

0.037

gMVP

0.32

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over