9-95456374-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP6

The NM_000264.5(PTCH1):​c.3208A>G​(p.Met1070Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.85
Variant links:
Genes affected
PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a transmembrane_region Helical (size 20) in uniprot entity PTC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000264.5
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 9-95456374-T-C is Benign according to our data. Variant chr9-95456374-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTCH1NM_000264.5 linkc.3208A>G p.Met1070Val missense_variant Exon 19 of 24 ENST00000331920.11 NP_000255.2 Q13635-1
PTCH1NM_001083603.3 linkc.3205A>G p.Met1069Val missense_variant Exon 19 of 24 ENST00000437951.6 NP_001077072.1 Q13635-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTCH1ENST00000331920.11 linkc.3208A>G p.Met1070Val missense_variant Exon 19 of 24 5 NM_000264.5 ENSP00000332353.6 Q13635-1
PTCH1ENST00000437951.6 linkc.3205A>G p.Met1069Val missense_variant Exon 19 of 24 5 NM_001083603.3 ENSP00000389744.2 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251268
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135818
show subpopulations
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:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461786
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727188
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 01, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Gorlin syndrome Benign:1
Mar 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
23
DANN
Benign
0.80
DEOGEN2
Benign
0.30
T;.;.;.;.;.;.
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.094
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.80
T;.;T;T;.;.;T
M_CAP
Benign
0.050
D
MetaRNN
Uncertain
0.55
D;D;D;D;D;D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
-1.1
N;.;.;.;.;.;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
0.34
N;N;N;N;N;N;N
REVEL
Uncertain
0.45
Sift
Benign
0.60
T;T;T;T;T;T;T
Sift4G
Benign
0.80
T;T;T;T;T;T;T
Polyphen
0.0040
B;.;.;B;B;.;B
Vest4
0.83
MutPred
0.60
Gain of catalytic residue at M1070 (P = 0.0028);.;.;.;.;.;.;
MVP
0.71
MPC
0.56
ClinPred
0.26
T
GERP RS
5.5
Varity_R
0.31
gMVP
0.87

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: rs768302786; hg19: chr9-98218656; API