rs587778687

chr7-129189250-C-Achr7-129189250-C-Gchr7-129189250-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_005631.5(SMO):c.99C>A(p.Ser33Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,223,170 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.844

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000257 (275/1071520) while in subpopulation NFE AF= 0.000283 (258/910416). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4_exome. There are 121 alleles in male gnomad4_exome subpopulation. Median coverage is 20. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMO	NM_005631.5	c.99C>A	p.Ser33Arg	missense_variant	1/12	ENST00000249373.8
SMO	XM_047420759.1	c.-406C>A		5_prime_UTR_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.99C>A	p.Ser33Arg	missense_variant	1/12	1	NM_005631.5	P1
SMO	ENST00000655644.1	c.99C>A	p.Ser33Arg	missense_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.0000857 AC: 13 AN: 151650 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000257 AC: 275 AN: 1071520 Hom.: 0 Cov.: 20 AF XY: 0.000237 AC XY: 121 AN XY: 510144

Gnomad4 AFR exome AF: 0.00

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: 0.000283

Gnomad4 OTH exome AF: 0.000394

GnomAD4 genome AF: 0.0000857 AC: 13 AN: 151650 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74056

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0066	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.046
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.69	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.30	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.27		Loss of glycosylation at S33 (P = 0.0034);
MVP		0.76
MPC		1.1
ClinPred		0.91	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.33

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: rs587778687; hg19: chr7-128829091; COSMIC: COSV105857293;