rs61746143

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005631.5(SMO):c.503G>A(p.Arg168His) variant causes a missense change. The variant allele was found at a frequency of 0.00452 in 1,603,900 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 125 hom. )

Consequence

SMO
NM_005631.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 5.28

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017337203).

BP6

Variant 7-129203555-G-A is Benign according to our data. Variant chr7-129203555-G-A is described in ClinVar as Benign. ClinVar VariationId is 135266.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 = 0.00302 (460/152312) while in subpopulation SAS AF = 0.0458 (221/4828). AF 95% confidence interval is 0.0408. There are 9 homozygotes in GnomAd4. There are 286 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMO	NM_005631.5 link	c.503G>A	p.Arg168His	missense_variant	Exon 2 of 12	ENST00000249373.8	NP_005622.1
SMO	XM_047420759.1 link	c.113G>A	p.Arg38His	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.503G>A	p.Arg168His	missense_variant	Exon 2 of 12	1	NM_005631.5	ENSP00000249373.3
SMO	ENST00000655644.1 link	n.*367G>A		non_coding_transcript_exon_variant	Exon 3 of 12			ENSP00000499377.1
SMO	ENST00000655644.1 link	n.*367G>A		3_prime_UTR_variant	Exon 3 of 12			ENSP00000499377.1

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

459

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0455

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00237

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00731

AC:

1747

AN:

239140

AF XY:

0.00975

show subpopulations

Gnomad AFR exome

AF:

0.000190

Gnomad AMR exome

AF:

0.00146

Gnomad ASJ exome

AF:

0.00613

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000410

Gnomad NFE exome

AF:

0.00243

Gnomad OTH exome

AF:

0.00384

GnomAD4 exome

AF:

0.00467

AC:

6784

AN:

1451588

Hom.:

125

Cov.:

AF XY:

0.00612

AC XY:

4420

AN XY:

722256

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33470

American (AMR)

AF:

0.00170

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00533

AC:

139

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0462

AC:

3960

AN:

85780

European-Finnish (FIN)

AF:

0.000588

AC:

AN:

44242

Middle Eastern (MID)

AF:

0.0153

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00197

AC:

2189

AN:

1111654

Other (OTH)

AF:

0.00481

AC:

290

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

411

822

1234

1645

2056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00302

AC:

460

AN:

152312

Hom.:

Cov.:

AF XY:

0.00384

AC XY:

286

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41558

American (AMR)

AF:

0.00229

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.0458

AC:

221

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00237

AC:

161

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00272

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00793

AC:

963

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00371

EpiControl

AF:

0.00368

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.094

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.017

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.6

PhyloP100

5.3

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.43

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.018

Polyphen

0.77

Vest4

0.36

MVP

0.86

MPC

1.7

ClinPred

0.052

GERP RS

4.4

Varity_R

0.26

gMVP

0.46

Mutation Taster

=82/18

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