7-129212147-C-T

Position:

• chr7-129212147-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005631.5(SMO):​c.2060C>T​(p.Pro687Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,557,082 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O: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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004938185).
• BP6: Variant 7-129212147-C-T is Benign according to our data. Variant chr7-129212147-C-T is described in ClinVar as [Benign]. Clinvar id is 135259.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00207 (315/152302) while in subpopulation AFR AF= 0.00719 (299/41574). AF 95% confidence interval is 0.00652. There are 2 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMO	NM_005631.5	c.2060C>T	p.Pro687Leu	missense_variant	12/12	ENST00000249373.8
SMO	XM_047420759.1	c.1670C>T	p.Pro557Leu	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.2060C>T	p.Pro687Leu	missense_variant	12/12	1	NM_005631.5	P1
	ENST00000466717.1	n.129+1270G>A		intron_variant, non_coding_transcript_variant		3
SMO	ENST00000475779.1	c.*364C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	3
SMO	ENST00000655644.1	c.*1815C>T		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 310 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00709

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000550 AC: 89 AN: 161682 Hom.: 0 AF XY: 0.000430 AC XY: 37 AN XY: 86026

Gnomad AFR exome AF: 0.00856

Gnomad AMR exome AF: 0.000356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000860

Gnomad SAS exome AF: 0.0000427

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000156

Gnomad OTH exome AF: 0.000440

GnomAD4 exome AF: 0.000243 AC: 342 AN: 1404780 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 149 AN XY: 693656

Gnomad4 AFR exome AF: 0.00842

Gnomad4 AMR exome AF: 0.000466

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.0000500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000129

Gnomad4 OTH exome AF: 0.000635

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74478

Gnomad4 AFR AF: 0.00719

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.00283

ESP6500AA AF: 0.00902 AC: 39

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000537 AC: 62

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2018

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.22
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.63
MPC		0.069
ClinPred		0.016	T
GERP RS		4.7
Varity_R		0.053
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55722779; hg19: chr7-128851988; COSMIC: COSV50825342; COSMIC: COSV50825342;