9-95468951-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000264.5(PTCH1):​c.2050G>A​(p.Glu684Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

1
7
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.77
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.024335325).
BP6
Variant 9-95468951-C-T is Benign according to our data. Variant chr9-95468951-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 215685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000552 (84/152184) while in subpopulation AFR AF= 0.0019 (79/41514). AF 95% confidence interval is 0.00156. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTCH1NM_000264.5 linkuse as main transcriptc.2050G>A p.Glu684Lys missense_variant 14/24 ENST00000331920.11 NP_000255.2 Q13635-1
PTCH1NM_001083603.3 linkuse as main transcriptc.2047G>A p.Glu683Lys missense_variant 14/24 ENST00000437951.6 NP_001077072.1 Q13635-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTCH1ENST00000331920.11 linkuse as main transcriptc.2050G>A p.Glu684Lys missense_variant 14/245 NM_000264.5 ENSP00000332353.6 Q13635-1
PTCH1ENST00000437951.6 linkuse as main transcriptc.2047G>A p.Glu683Lys missense_variant 14/245 NM_001083603.3 ENSP00000389744.2 Q13635-2

Frequencies

GnomAD3 genomes
AF:
0.000552
AC:
84
AN:
152066
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00191
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000183
AC:
46
AN:
251434
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00258
Gnomad AMR exome
AF:
0.0000289
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:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000746
AC:
109
AN:
1461868
Hom.:
0
Cov.:
33
AF XY:
0.0000619
AC XY:
45
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00275
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000552
AC:
84
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.000484
AC XY:
36
AN XY:
74396
show subpopulations
Gnomad4 AFR
AF:
0.00190
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000127
Hom.:
0
Bravo
AF:
0.000638
ESP6500AA
AF:
0.00250
AC:
11
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000206
AC:
25
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submittercurationSema4, Sema4Feb 28, 2022- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 11, 2019This 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. -
PTCH1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 27, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Gorlin syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxSep 05, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.;.;.;.;.;.;.
Eigen
Benign
-0.19
Eigen_PC
Benign
0.014
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;.;D;D;.;.;D;D
M_CAP
Uncertain
0.090
D
MetaRNN
Benign
0.024
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
1.6
L;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.73
N;N;N;N;N;N;N;N
REVEL
Uncertain
0.52
Sift
Benign
0.19
T;T;T;T;T;T;T;D
Sift4G
Benign
0.48
T;T;T;T;T;T;T;.
Polyphen
0.24
B;B;B;B;B;B;B;.
Vest4
0.69
MVP
0.67
MPC
0.63
ClinPred
0.013
T
GERP RS
4.8
Varity_R
0.10
gMVP
0.33

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: rs62637629; hg19: chr9-98231233; COSMIC: COSV104648288; API