chr9-95468829-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000264.5(PTCH1):ā€‹c.2172G>Cā€‹(p.Glu724Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E724K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000021 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.58
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 Likely_benign. Variant got -6 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=0.16036624).
BP6
Variant 9-95468829-C-G is Benign according to our data. Variant chr9-95468829-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453817.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTCH1NM_000264.5 linkuse as main transcriptc.2172G>C p.Glu724Asp missense_variant 14/24 ENST00000331920.11 NP_000255.2 Q13635-1
PTCH1NM_001083603.3 linkuse as main transcriptc.2169G>C p.Glu723Asp 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.2172G>C p.Glu724Asp missense_variant 14/245 NM_000264.5 ENSP00000332353.6 Q13635-1
PTCH1ENST00000437951.6 linkuse as main transcriptc.2169G>C p.Glu723Asp missense_variant 14/245 NM_001083603.3 ENSP00000389744.2 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251478
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135910
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461890
Hom.:
0
Cov.:
33
AF XY:
0.0000165
AC XY:
12
AN XY:
727244
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:
0.0000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Basal cell carcinoma, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMay 16, 2023- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 04, 2024The p.E724D variant (also known as c.2172G>C), located in coding exon 14 of the PTCH1 gene, results from a G to C substitution at nucleotide position 2172. The glutamic acid at codon 724 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Gorlin syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.086
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.31
T;.;.;.;.;.;.
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.21
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.82
T;.;T;T;.;.;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.16
T;T;T;T;T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
0.77
N;.;.;.;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-0.12
N;N;N;N;N;N;N
REVEL
Benign
0.25
Sift
Benign
0.47
T;T;T;T;T;T;T
Sift4G
Benign
0.51
T;T;T;T;T;T;T
Polyphen
0.0010
B;B;B;B;B;B;B
Vest4
0.34
MutPred
0.34
Gain of ubiquitination at K729 (P = 0.0882);.;.;.;.;.;.;
MVP
0.51
MPC
0.50
ClinPred
0.26
T
GERP RS
3.9
Varity_R
0.055
gMVP
0.51

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: rs747274181; hg19: chr9-98231111; COSMIC: COSV59463960; COSMIC: COSV59463960; API