7-129211755-C-G

Position:

• chr7-129211755-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BS1_Supporting

The NM_005631.5(SMO):​c.1921C>G​(p.Pro641Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,613,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: SMO NM_005631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 7.40

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000388 (59/152132) while in subpopulation NFE AF= 0.000735 (50/68030). AF 95% confidence interval is 0.000572. There are 0 homozygotes in gnomad4. There are 25 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.1921C>G	p.Pro641Ala	missense_variant	11/12	ENST00000249373.8
SMO	XM_047420759.1	c.1531C>G	p.Pro511Ala	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMO	ENST00000249373.8	c.1921C>G	p.Pro641Ala	missense_variant	11/12	1	NM_005631.5	P1
	ENST00000466717.1	n.130-1575G>C		intron_variant, non_coding_transcript_variant		3
SMO	ENST00000475779.1	c.*225C>G		3_prime_UTR_variant, NMD_transcript_variant	4/5	3
SMO	ENST00000655644.1	c.*1676C>G		3_prime_UTR_variant, NMD_transcript_variant	11/12

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000430 AC: 108 AN: 251432 Hom.: 1 AF XY: 0.000368 AC XY: 50 AN XY: 135898

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000685 AC: 1002 AN: 1461826 Hom.: 1 Cov.: 32 AF XY: 0.000681 AC XY: 495 AN XY: 727214

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000827

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74320

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000959

Alfa AF: 0.000702 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2023

Reported in families with variable cancer phenotypes including medulloblastoma, nonsmall-cell lung cancer, and colorectal cancer; suggested as a cancer susceptibility variant (Kool et al., 2014; Tsao et al., 2017; Toma et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Tsao2017[Abstract], Tsao2017[CaseReport], 24728327, 24651015, 31525256, 27535533) -

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	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.93
MPC		0.20
ClinPred		0.18	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.36

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: rs146200641; hg19: chr7-128851596; COSMIC: COSV50852667; COSMIC: COSV50852667;