rs41303402

chr7-129203437-G-Achr7-129203437-G-Cchr7-129203437-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_005631.5(SMO):c.385G>A(p.Val129Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000283 in 1,566,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23349479).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152318) while in subpopulation NFE AF= 0.000323 (22/68022). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMO	NM_005631.5	c.385G>A	p.Val129Ile	missense_variant	2/12	ENST00000249373.8
SMO	XM_047420759.1	c.-6G>A		5_prime_UTR_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.385G>A	p.Val129Ile	missense_variant	2/12	1	NM_005631.5	P1
SMO	ENST00000655644.1	c.*249G>A		3_prime_UTR_variant, NMD_transcript_variant	3/12

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000102 AC: 18 AN: 176590 Hom.: 0 AF XY: 0.0000956 AC XY: 9 AN XY: 94188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000624

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000297 AC: 420 AN: 1413818 Hom.: 1 Cov.: 32 AF XY: 0.000312 AC XY: 218 AN XY: 699006

Gnomad4 AFR exome AF: 0.0000926

Gnomad4 AMR exome AF: 0.0000266

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000403

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.000188

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74496

Gnomad4 AFR AF: 0.0000240

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: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; A case-control genotyping study suggested this allele may protect against risk for basal cell carcinoma (Lesiak et al., 2016), but allele frequency was much higher than that reported in large population cohorts or observed in presumably healthy individuals tested at GeneDx, calling these results into question; This variant is associated with the following publications: (PMID: 26590974) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.36
Sift	Benign	0.22	T
Sift4G	Benign	0.15	T
Polyphen		0.56	P
Vest4		0.32
MVP		0.66
MPC		0.57
ClinPred		0.14	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.62

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: rs41303402; hg19: chr7-128843278; COSMIC: COSV99976911; COSMIC: COSV99976911;