9-95461881-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000264.5(PTCH1):​c.2678G>A​(p.Arg893His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,614,206 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00026 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 7 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

1
7
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:8

Conservation

PhyloP100: 2.39
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 Benign. Variant got -17 ACMG points.

PM1
In a topological_domain Extracellular (size 257) in uniprot entity PTC1_HUMAN there are 24 pathogenic changes around while only 5 benign (83%) in NM_000264.5
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=0.008085132).
BP6
Variant 9-95461881-C-T is Benign according to our data. Variant chr9-95461881-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 41656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95461881-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000256 (39/152316) while in subpopulation EAS AF= 0.00599 (31/5178). AF 95% confidence interval is 0.00433. There are 1 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTCH1NM_000264.5 linkuse as main transcriptc.2678G>A p.Arg893His missense_variant 16/24 ENST00000331920.11 NP_000255.2
PTCH1NM_001083603.3 linkuse as main transcriptc.2675G>A p.Arg892His missense_variant 16/24 ENST00000437951.6 NP_001077072.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTCH1ENST00000331920.11 linkuse as main transcriptc.2678G>A p.Arg893His missense_variant 16/245 NM_000264.5 ENSP00000332353 A2Q13635-1
PTCH1ENST00000437951.6 linkuse as main transcriptc.2675G>A p.Arg892His missense_variant 16/245 NM_001083603.3 ENSP00000389744 Q13635-2

Frequencies

GnomAD3 genomes
AF:
0.000256
AC:
39
AN:
152198
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00597
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000597
AC:
150
AN:
251432
Hom.:
2
AF XY:
0.000581
AC XY:
79
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.000198
Gnomad EAS exome
AF:
0.00696
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000395
AC:
577
AN:
1461890
Hom.:
7
Cov.:
32
AF XY:
0.000408
AC XY:
297
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.000191
Gnomad4 EAS exome
AF:
0.0119
Gnomad4 SAS exome
AF:
0.000325
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.000464
GnomAD4 genome
AF:
0.000256
AC:
39
AN:
152316
Hom.:
1
Cov.:
32
AF XY:
0.000255
AC XY:
19
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00599
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000454
Hom.:
0
Bravo
AF:
0.000291
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.000585
AC:
71
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:4
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 26, 2019This variant is associated with the following publications: (PMID: 29642553, 24942795, 16109989, 22703879) -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 05, 2017- -
Uncertain significance, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 28, 2022- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024PTCH1: BS1, BS2 -
Gorlin syndrome Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 20, 2018This 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. -
Holoprosencephaly 7 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.17
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.33
T;.;.;.;.;.;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.88
D;.;D;D;.;.;D
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.0081
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.021
D
MutationAssessor
Benign
1.7
L;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.2
N;N;N;N;N;N;N
REVEL
Uncertain
0.41
Sift
Benign
0.13
T;T;T;T;T;T;T
Sift4G
Benign
0.12
T;T;T;T;T;T;T
Polyphen
0.99
D;.;.;D;D;.;D
Vest4
0.28
MVP
0.86
MPC
0.68
ClinPred
0.054
T
GERP RS
4.4
Varity_R
0.12
gMVP
0.74

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: rs138154222; hg19: chr9-98224163; COSMIC: COSV59484322; COSMIC: COSV59484322; API