Genetic Variant SMO:p.Arg168Leu (chr7-129203555-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005631.5(SMO):c.503G>T(p.Arg168Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMO
NM_005631.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.28

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMO	NM_005631.5 link	c.503G>T	p.Arg168Leu	missense_variant	Exon 2 of 12	ENST00000249373.8	NP_005622.1
SMO	XM_047420759.1 link	c.113G>T	p.Arg38Leu	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>T	p.Arg168Leu	missense_variant	Exon 2 of 12	1	NM_005631.5	ENSP00000249373.3
SMO	ENST00000655644.1 link	n.*367G>T		non_coding_transcript_exon_variant	Exon 3 of 12			ENSP00000499377.1
SMO	ENST00000655644.1 link	n.*367G>T		3_prime_UTR_variant	Exon 3 of 12			ENSP00000499377.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722268

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

85788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111662

Other (OTH)

AF:

0.00

AC:

AN:

60282

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.65

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.4

PhyloP100

5.3

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.46

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.021

Polyphen

0.080

Vest4

0.56

MutPred

0.62

Loss of disorder (P = 0.0339);

MVP

0.83

MPC

1.4

ClinPred

0.99

GERP RS

4.4

Varity_R

0.48

gMVP

0.66

Mutation Taster

=72/28

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over