dbSNP rs143083812: SMO:p.Arg173Ser (chr7-129203569-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005631.5(SMO):c.517C>A(p.Arg173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. R173H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SMO
NM_005631.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.28

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1741418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMO	NM_005631.5 link	c.517C>A	p.Arg173Ser	missense_variant	Exon 2 of 12	ENST00000249373.8	NP_005622.1	Q99835
SMO	XM_047420759.1 link	c.127C>A	p.Arg43Ser	missense_variant	Exon 3 of 13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMO	ENST00000249373.8 link	c.517C>A	p.Arg173Ser	missense_variant	Exon 2 of 12	1	NM_005631.5	ENSP00000249373.3	Q99835
SMO	ENST00000655644.1 link	n.*381C>A		non_coding_transcript_exon_variant	Exon 3 of 12			ENSP00000499377.1	A0A590UJE7
SMO	ENST00000655644.1 link	n.*381C>A		3_prime_UTR_variant	Exon 3 of 12			ENSP00000499377.1	A0A590UJE7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449608

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

85738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111496

Other (OTH)

AF:

0.00

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.045

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.63

M_CAP

Benign

0.028

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.7

PhyloP100

1.3

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.88

REVEL

Benign

0.15

Sift

Benign

0.40

Sift4G

Benign

0.41

Polyphen

0.023

Vest4

0.29

MutPred

0.53

Gain of phosphorylation at R173 (P = 0.1459);

MVP

0.72

MPC

0.75

ClinPred

0.68

GERP RS

3.5

Varity_R

0.22

gMVP

0.50

Mutation Taster

=78/22

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over