9-95461881-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000264.5(PTCH1):​c.2678G>C​(p.Arg893Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R893H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PTCH1
NM_000264.5 missense

Scores

1
6
12

Clinical Significance

Not reported in ClinVar

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTCH1NM_000264.5 linkc.2678G>C p.Arg893Pro missense_variant 16/24 ENST00000331920.11 NP_000255.2 Q13635-1
PTCH1NM_001083603.3 linkc.2675G>C p.Arg892Pro missense_variant 16/24 ENST00000437951.6 NP_001077072.1 Q13635-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTCH1ENST00000331920.11 linkc.2678G>C p.Arg893Pro missense_variant 16/245 NM_000264.5 ENSP00000332353.6 Q13635-1
PTCH1ENST00000437951.6 linkc.2675G>C p.Arg892Pro missense_variant 16/245 NM_001083603.3 ENSP00000389744.2 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T;.;.;.;.;.;.
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.095
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.82
T;.;T;T;.;.;T
M_CAP
Benign
0.035
D
MetaRNN
Uncertain
0.69
D;D;D;D;D;D;D
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
1.4
L;.;.;.;.;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.66
N;N;N;N;N;N;N
REVEL
Uncertain
0.49
Sift
Benign
0.28
T;T;T;T;T;T;T
Sift4G
Benign
0.28
T;T;T;T;T;T;T
Polyphen
0.011
B;.;.;B;B;.;B
Vest4
0.67
MutPred
0.61
Gain of ubiquitination at K895 (P = 0.0409);.;.;.;.;.;.;
MVP
0.98
MPC
0.80
ClinPred
0.81
D
GERP RS
4.4
Varity_R
0.60
gMVP
0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-98224163; API