Variant chr7-129189327-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005631.5(SMO):c.176C>A(p.Pro59Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,352,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SMO
NM_005631.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32320213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMO	NM_005631.5 linkuse as main transcript	c.176C>A	p.Pro59Gln	missense_variant	1/12	ENST00000249373.8	NP_005622.1	Q99835
SMO	XM_047420759.1 linkuse as main transcript	c.-329C>A		5_prime_UTR_variant	1/13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMO	ENST00000249373.8 linkuse as main transcript	c.176C>A	p.Pro59Gln	missense_variant	1/12	1	NM_005631.5	ENSP00000249373.3		Q99835
SMO	ENST00000655644.1 linkuse as main transcript	n.176C>A		non_coding_transcript_exon_variant	1/12			ENSP00000499377.1		A0A590UJE7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000989

AC:

AN:

101150

Hom.:

AF XY:

0.00

AC XY:

AN XY:

56738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000272

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000148

AC:

AN:

1352922

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

666978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000131

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.38e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The c.176C>A (p.P59Q) alteration is located in exon 1 (coding exon 1) of the SMO gene. This alteration results from a C to A substitution at nucleotide position 176, causing the proline (P) at amino acid position 59 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.47

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.0

REVEL

Benign

0.23

Sift

Benign

0.031

Sift4G

Pathogenic

0.0

Polyphen

0.59

Vest4

0.24

MutPred

0.23

Loss of glycosylation at P59 (P = 0.0018);

MVP

0.72

MPC

1.5

ClinPred

0.56

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

gMVP

0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over