7-129212264-G-A

Position:

chr7-129212264-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The ENST00000249373.8(SMO):c.2177G>A(p.Arg726Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,609,762 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

SMO
ENST00000249373.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.560

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15514883).

BP6

Variant 7-129212264-G-A is Benign according to our data. Variant chr7-129212264-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135263.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, not_provided=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000729 (111/152212) while in subpopulation NFE AF= 0.00132 (90/68036). AF 95% confidence interval is 0.0011. There are 1 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMO	NM_005631.5 linkuse as main transcript	c.2177G>A	p.Arg726Gln	missense_variant	12/12	ENST00000249373.8	NP_005622.1
SMO	XM_047420759.1 linkuse as main transcript	c.1787G>A	p.Arg596Gln	missense_variant	13/13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SMO	ENST00000249373.8 linkuse as main transcript	c.2177G>A	p.Arg726Gln	missense_variant	12/12	1	NM_005631.5	ENSP00000249373	P1
	ENST00000466717.1 linkuse as main transcript	n.129+1153C>T		intron_variant, non_coding_transcript_variant		3
SMO	ENST00000655644.1 linkuse as main transcript	c.*1932G>A		3_prime_UTR_variant, NMD_transcript_variant	12/12			ENSP00000499377

Frequencies

GnomAD3 genomes

AF:

0.000729

AC:

111

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000587

AC:

141

AN:

240020

Hom.:

AF XY:

0.000545

AC XY:

AN XY:

130334

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:

0.0000334

Gnomad FIN exome

AF:

0.00184

Gnomad NFE exome

AF:

0.000921

Gnomad OTH exome

AF:

0.000512

GnomAD4 exome

AF:

0.000554

AC:

808

AN:

1457550

Hom.:

Cov.:

AF XY:

0.000586

AC XY:

425

AN XY:

724878

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00198

Gnomad4 NFE exome

AF:

0.000605

Gnomad4 OTH exome

AF:

0.000482

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152212

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00132

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000602

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Curry-Jones syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

SMO: BP4 -

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

0.075

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.90

MutationTaster

Benign

0.96

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

REVEL

Pathogenic

0.70

Sift

Benign

0.092

Sift4G

Benign

0.39

Polyphen

0.079

Vest4

0.66

MVP

0.72

MPC

0.088

ClinPred

0.078

GERP RS

5.4

Varity_R

0.053

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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