rs111694017

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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 Benign. Variant got -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 id is 135269.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Benign=2}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMO	NM_005631.5 link	c.808G>A	p.Val270Ile	missense_variant	4/12	ENST00000249373.8	NP_005622.1	Q99835
SMO	XM_047420759.1 link	c.418G>A	p.Val140Ile	missense_variant	5/13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMO	ENST00000249373.8 link	c.808G>A	p.Val270Ile	missense_variant	4/12	1	NM_005631.5	ENSP00000249373.3	Q99835
SMO	ENST00000655644.1 link	n.*672G>A		non_coding_transcript_exon_variant	5/12			ENSP00000499377.1	A0A590UJE7
SMO	ENST00000655644.1 link	n.*672G>A		3_prime_UTR_variant	5/12			ENSP00000499377.1	A0A590UJE7

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

GnomAD3 exomes

AF:

0.00694

AC:

1745

AN:

251326

Hom.:

AF XY:

0.00704

AC XY:

956

AN XY:

135848

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 SAS exome

AF:

0.00549

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

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.00250

Gnomad4 ASJ exome

AF:

0.00957

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00553

Gnomad4 FIN exome

AF:

0.00643

Gnomad4 NFE exome

AF:

0.0106

Gnomad4 OTH exome

AF:

0.00813

GnomAD4 genome

AF:

0.00733

AC:

1117

AN:

152322

Hom.:

Cov.:

AF XY:

0.00667

AC XY:

497

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.00565

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00975

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SMO: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

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

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

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

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