NM_005631.5:c.1939C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005631.5(SMO):c.1939C>T(p.Pro647Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00805 in 1,581,862 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0083 ( 58 hom. )

Consequence

SMO
NM_005631.5 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 6.67

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:

ENSG00000243230 (HGNC:):

ENSG00000243230 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077956915).

BP6

Variant 7-129212026-C-T is Benign according to our data. Variant chr7-129212026-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-129212026-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00576 (877/152236) while in subpopulation NFE AF= 0.00975 (663/67988). AF 95% confidence interval is 0.00914. There are 3 homozygotes in gnomad4. There are 381 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMO	NM_005631.5 link	c.1939C>T	p.Pro647Ser	missense_variant, splice_region_variant	Exon 12 of 12	ENST00000249373.8	NP_005622.1	Q99835
SMO	XM_047420759.1 link	c.1549C>T	p.Pro517Ser	missense_variant, splice_region_variant	Exon 13 of 13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMO	ENST00000249373.8 link	c.1939C>T	p.Pro647Ser	missense_variant, splice_region_variant	Exon 12 of 12	1	NM_005631.5	ENSP00000249373.3		Q99835

Frequencies

GnomAD3 genomes

AF:

0.00577

AC:

877

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00975

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00503

AC:

1071

AN:

212758

Hom.:

AF XY:

0.00527

AC XY:

609

AN XY:

115628

show subpopulations

Gnomad AFR exome

AF:

0.00108

Gnomad AMR exome

AF:

0.00300

Gnomad ASJ exome

AF:

0.00583

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00130

Gnomad FIN exome

AF:

0.00201

Gnomad NFE exome

AF:

0.00836

Gnomad OTH exome

AF:

0.00583

GnomAD4 exome

AF:

0.00830

AC:

11862

AN:

1429626

Hom.:

Cov.:

AF XY:

0.00817

AC XY:

5798

AN XY:

710046

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.00343

Gnomad4 ASJ exome

AF:

0.00740

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00143

Gnomad4 FIN exome

AF:

0.00275

Gnomad4 NFE exome

AF:

0.00982

Gnomad4 OTH exome

AF:

0.00675

GnomAD4 genome

AF:

0.00576

AC:

877

AN:

152236

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

381

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00144

Gnomad4 AMR

AF:

0.00517

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00975

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00819

Hom.:

Bravo

AF:

0.00634

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.00435

AC:

527

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 01, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMO: BS2 -

Hamartoma of hypothalamus

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

European Non-Finnish population allele frequency is 0.7881% (rs34545616, 1071/212758 alleles, 3 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.81

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.10

REVEL

Benign

0.27

Sift

Benign

0.17

Sift4G

Benign

0.25

Polyphen

1.0

Vest4

0.43

MVP

0.88

MPC

0.22

ClinPred

0.0096

GERP RS

5.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.076

gMVP

0.42

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