9-95478078-C-T
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM5PP2BP6_Very_StrongBS2
The NM_000264.5(PTCH1):c.1324G>A(p.Val442Met) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V442E) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
PTCH1
NM_000264.5 missense
NM_000264.5 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 5.61
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-95478077-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 3242226.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.
BP6
Variant 9-95478078-C-T is Benign according to our data. Variant chr9-95478078-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 453784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTCH1 | NM_000264.5 | c.1324G>A | p.Val442Met | missense_variant | 9/24 | ENST00000331920.11 | |
PTCH1 | NM_001083603.3 | c.1321G>A | p.Val441Met | missense_variant | 9/24 | ENST00000437951.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.1324G>A | p.Val442Met | missense_variant | 9/24 | 5 | NM_000264.5 | A2 | |
PTCH1 | ENST00000437951.6 | c.1321G>A | p.Val441Met | missense_variant | 9/24 | 5 | NM_001083603.3 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152166Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251486Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
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GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727244
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74456
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Gorlin syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;.;.;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N;N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;.
Polyphen
D;D;D;D;D;D;D;.
Vest4
MutPred
Gain of sheet (P = 0.0266);.;.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at