7-129206557-C-T

Variant names:

• chr7-129206557-C-T
• rs879255280
• NM_005631.5:c.1234C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_005631.5(SMO):​c.1234C>T​(p.Leu412Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.97

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 27) in uniprot entity SMO_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005631.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 7-129206557-C-T is Pathogenic according to our data. Variant chr7-129206557-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 245609.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-129206557-C-T is described in Lovd as [Pathogenic]. Variant chr7-129206557-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMO	NM_005631.5	c.1234C>T	p.Leu412Phe	missense_variant	Exon 6 of 12	ENST00000249373.8	NP_005622.1
SMO	XM_047420759.1	c.844C>T	p.Leu282Phe	missense_variant	Exon 7 of 13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMO	ENST00000249373.8	c.1234C>T	p.Leu412Phe	missense_variant	Exon 6 of 12	1	NM_005631.5	ENSP00000249373.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Curry-Jones syndrome Pathogenic:2

Oct 11, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 22, 2019

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A somatic c.1234C>T (p.L412F) pathogenic variant in the SMO gene was detected in this individual’s affected skin sample. Whole genome sequencing analysis of this region on this individual’s unaffected skin sample and parental samples for this individual did not detect the c.1234C>T (p.L412F) change, suggesting it arose in this individual’s somatic tissues as a mosaic change. The c.1234C>T (p.L412F) variant has been reported as a recurrent somatic mutation in multiple affected individuals [PMID 27236920]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.80
Sift	Benign	0.10	T
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.69		Loss of helix (P = 0.3949);
MVP		0.91
MPC		1.3
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.67
gMVP		0.86

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

Other links and lift over

dbSNP: rs879255280; hg19: chr7-128846398; COSMIC: COSV50824425; COSMIC: COSV50824425;