chr7-129206557-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L412P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 5.97
• Publications: 110 publications found

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
• mosaic SMO syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• congenital hypothalamic hamartoma syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• 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 VariationId is 245609.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMO	NM_005631.5	MANE Select	c.1234C>T	p.Leu412Phe	missense	Exon 6 of 12	NP_005622.1	Q99835

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMO	ENST00000249373.8	TSL:1 MANE Select	c.1234C>T	p.Leu412Phe	missense	Exon 6 of 12	ENSP00000249373.3	Q99835
	SMO	ENST00000925241.1		c.1234C>T	p.Leu412Phe	missense	Exon 6 of 12	ENSP00000595300.1
	SMO	ENST00000925243.1		c.1234C>T	p.Leu412Phe	missense	Exon 6 of 12	ENSP00000595302.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Curry-Jones syndrome (2)
-	-	-	Medulloblastoma WNT activated (1)
-	-	-	Meningioma (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.0
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
Mutation Taster		=24/76	disease causing (ClinVar)

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

Other links and lift over

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