chr7-129189357-C-A

Position:

• chr7-129189357-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005631.5(SMO):​c.206C>A​(p.Pro69His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,377,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.706

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3436895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMO	NM_005631.5	c.206C>A	p.Pro69His	missense_variant	1/12	ENST00000249373.8
SMO	XM_047420759.1	c.-299C>A		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.206C>A	p.Pro69His	missense_variant	1/12	1	NM_005631.5	P1
SMO	ENST00000655644.1	c.206C>A	p.Pro69His	missense_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1377174 Hom.: 0 Cov.: 31 AF XY: 0.00000294 AC XY: 2 AN XY: 679600

Gnomad4 AFR exome AF: 0.0000658

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.206C>A (p.P69H) alteration is located in exon 1 (coding exon 1) of the SMO gene. This alteration results from a C to A substitution at nucleotide position 206, causing the proline (P) at amino acid position 69 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.060	N
REVEL	Benign	0.15
Sift	Benign	0.20	T
Sift4G	Uncertain	0.022	D
Polyphen		0.14	B
Vest4		0.14
MutPred		0.30		Loss of disorder (P = 0.076);
MVP		0.65
MPC		0.70
ClinPred		0.32	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.35

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: rs1189276452; hg19: chr7-128829198;