chr7-129212026-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

15 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:

ENSG00000243230 (HGNC:):

ENSG00000243230 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 135575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005631.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMO	NM_005631.5	MANE Select	c.1939C>T	p.Pro647Ser	missense splice_region	Exon 12 of 12	NP_005622.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMO	ENST00000249373.8	TSL:1 MANE Select	c.1939C>T	p.Pro647Ser	missense splice_region	Exon 12 of 12	ENSP00000249373.3
SMO	ENST00000475779.1	TSL:3	n.*243C>T		splice_region non_coding_transcript_exon	Exon 5 of 5	ENSP00000420749.1
SMO	ENST00000655644.1		n.*1694C>T		splice_region non_coding_transcript_exon	Exon 12 of 12	ENSP00000499377.1

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

GnomAD2 exomes

AF:

0.00503

AC:

1071

AN:

212758

AF XY:

0.00527

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 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

African (AFR)

AF:

0.00158

AC:

AN:

32992

American (AMR)

AF:

0.00343

AC:

147

AN:

42888

Ashkenazi Jewish (ASJ)

AF:

0.00740

AC:

187

AN:

25268

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38932

South Asian (SAS)

AF:

0.00143

AC:

119

AN:

83032

European-Finnish (FIN)

AF:

0.00275

AC:

106

AN:

38592

Middle Eastern (MID)

AF:

0.00368

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00982

AC:

10827

AN:

1102646

Other (OTH)

AF:

0.00675

AC:

402

AN:

59564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

575

1150

1725

2300

2875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

416

832

1248

1664

2080

<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

AF:

0.00576

AC:

877

AN:

152236

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

381

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41552

American (AMR)

AF:

0.00517

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00228

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00975

AC:

663

AN:

67988

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00809

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hamartoma of hypothalamus (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

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

PhyloP100

6.7

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

Mutation Taster

=54/46

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over