rs111694017

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005631.5(SMO):c.808G>A(p.Val270Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00909 in 1,613,916 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0073 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0093 ( 74 hom. )

Consequence

SMO
NM_005631.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2O:1

Conservation

PhyloP100: 4.68

Publications

22 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012343407).

BP6

Variant 7-129205670-G-A is Benign according to our data. Variant chr7-129205670-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135269.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00733 (1117/152322) while in subpopulation NFE AF = 0.0117 (795/68032). AF 95% confidence interval is 0.011. There are 10 homozygotes in GnomAd4. There are 497 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005631.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMO	NM_005631.5	MANE Select	c.808G>A	p.Val270Ile	missense	Exon 4 of 12	NP_005622.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMO	ENST00000249373.8	TSL:1 MANE Select	c.808G>A	p.Val270Ile	missense	Exon 4 of 12	ENSP00000249373.3
SMO	ENST00000655644.1		n.*672G>A		non_coding_transcript_exon	Exon 5 of 12	ENSP00000499377.1
SMO	ENST00000655644.1		n.*672G>A		3_prime_UTR	Exon 5 of 12	ENSP00000499377.1

Frequencies

GnomAD3 genomes

AF:

0.00735

AC:

1118

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00694

AC:

1745

AN:

251326

AF XY:

0.00704

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00558

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00928

AC:

13560

AN:

1461594

Hom.:

Cov.:

AF XY:

0.00929

AC XY:

6757

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33480

American (AMR)

AF:

0.00250

AC:

112

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00957

AC:

250

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00553

AC:

477

AN:

86256

European-Finnish (FIN)

AF:

0.00643

AC:

342

AN:

53200

Middle Eastern (MID)

AF:

0.00902

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0106

AC:

11784

AN:

1111940

Other (OTH)

AF:

0.00813

AC:

491

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

715

1430

2144

2859

3574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.00733

AC:

1117

AN:

152322

Hom.:

Cov.:

AF XY:

0.00667

AC XY:

497

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

41572

American (AMR)

AF:

0.00340

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00559

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

795

AN:

68032

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00938

Hom.:

Bravo

AF:

0.00685

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.0126

AC:

108

ExAC

AF:

0.00741

AC:

900

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00911

EpiControl

AF:

0.00895

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.36

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.39

PhyloP100

4.7

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.26

REVEL

Uncertain

0.37

Sift

Benign

1.0

Sift4G

Benign

0.63

Polyphen

0.047

Vest4

0.21

MVP

0.74

MPC

0.51

ClinPred

0.016

GERP RS

5.6

Varity_R

0.11

gMVP

0.29

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over