7-129210997-G-T

Variant names:

• chr7-129210997-G-T
• rs121918348
• NM_005631.5:c.1685G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_005631.5(SMO):​c.1685G>T​(p.Arg562Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R562Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.72
• Publications: 0 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

ENSG00000243230 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-129210997-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8118.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMO	NM_005631.5	c.1685G>T	p.Arg562Leu	missense_variant	Exon 10 of 12	ENST00000249373.8	NP_005622.1
SMO	XM_047420759.1	c.1295G>T	p.Arg432Leu	missense_variant	Exon 11 of 13		XP_047276715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMO	ENST00000249373.8	c.1685G>T	p.Arg562Leu	missense_variant	Exon 10 of 12	1	NM_005631.5	ENSP00000249373.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.35		Loss of MoRF binding (P = 0.0114);
MVP		0.88
MPC		0.21
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.79
Mutation Taster		=21/79	disease causing

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: rs121918348; hg19: chr7-128850838;