NM_005631.5:c.1234C>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
• 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

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

Selected	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

Ensembl Transcripts

Selected	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
	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 as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

View on ClinVar

Computational scores

Other links and lift over

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