7-129189311-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_005631.5(SMO):​c.160G>A​(p.Val54Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000854 in 1,483,176 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00061 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00088 ( 1 hom. )

Consequence

SMO
NM_005631.5 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.88
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.106022775).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000611 (93/152146) while in subpopulation NFE AF= 0.00106 (72/67960). AF 95% confidence interval is 0.000862. There are 1 homozygotes in gnomad4. There are 35 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 Protein UniProt
SMONM_005631.5 linkuse as main transcriptc.160G>A p.Val54Met missense_variant 1/12 ENST00000249373.8 NP_005622.1 Q99835
SMOXM_047420759.1 linkuse as main transcriptc.-345G>A 5_prime_UTR_premature_start_codon_gain_variant 1/13 XP_047276715.1
SMOXM_047420759.1 linkuse as main transcriptc.-345G>A 5_prime_UTR_variant 1/13 XP_047276715.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMOENST00000249373.8 linkuse as main transcriptc.160G>A p.Val54Met missense_variant 1/121 NM_005631.5 ENSP00000249373.3 Q99835
SMOENST00000655644.1 linkuse as main transcriptn.160G>A non_coding_transcript_exon_variant 1/12 ENSP00000499377.1 A0A590UJE7

Frequencies

GnomAD3 genomes
AF:
0.000618
AC:
94
AN:
152036
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000217
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000947
Gnomad MID
AF:
0.00955
Gnomad NFE
AF:
0.00106
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000546
AC:
45
AN:
82464
Hom.:
0
AF XY:
0.000532
AC XY:
25
AN XY:
46988
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000296
Gnomad ASJ exome
AF:
0.000696
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000181
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000957
Gnomad OTH exome
AF:
0.00160
GnomAD4 exome
AF:
0.000882
AC:
1174
AN:
1331030
Hom.:
1
Cov.:
31
AF XY:
0.000885
AC XY:
580
AN XY:
655670
show subpopulations
Gnomad4 AFR exome
AF:
0.000187
Gnomad4 AMR exome
AF:
0.000283
Gnomad4 ASJ exome
AF:
0.000702
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000191
Gnomad4 FIN exome
AF:
0.000335
Gnomad4 NFE exome
AF:
0.00100
Gnomad4 OTH exome
AF:
0.000974
GnomAD4 genome
AF:
0.000611
AC:
93
AN:
152146
Hom.:
1
Cov.:
32
AF XY:
0.000471
AC XY:
35
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000947
Gnomad4 NFE
AF:
0.00106
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000703
Hom.:
0
Bravo
AF:
0.000586
ExAC
AF:
0.000130
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 14, 2019In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27793025, 29533785, 28838384) -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalAug 19, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.39
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.61
T
M_CAP
Pathogenic
0.94
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
0.0
N
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-0.19
N
REVEL
Benign
0.15
Sift
Benign
0.12
T
Sift4G
Benign
0.062
T
Polyphen
0.22
B
Vest4
0.10
MVP
0.70
MPC
1.2
ClinPred
0.075
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.082
gMVP
0.19

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs541359801; hg19: chr7-128829152; COSMIC: COSV105069781; API