chr9-95447213-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000264.5(PTCH1):​c.4043A>C​(p.Asn1348Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. N1348D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

PTCH1
NM_000264.5 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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=0.16131827).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTCH1NM_000264.5 linkuse as main transcriptc.4043A>C p.Asn1348Thr missense_variant 23/24 ENST00000331920.11
PTCH1NM_001083603.3 linkuse as main transcriptc.4040A>C p.Asn1347Thr missense_variant 23/24 ENST00000437951.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTCH1ENST00000331920.11 linkuse as main transcriptc.4043A>C p.Asn1348Thr missense_variant 23/245 NM_000264.5 A2Q13635-1
PTCH1ENST00000437951.6 linkuse as main transcriptc.4040A>C p.Asn1347Thr missense_variant 23/245 NM_001083603.3 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.021
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
T;.;.;.;.;.;.
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.049
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.70
T;.;T;T;.;.;T
M_CAP
Benign
0.069
D
MetaRNN
Benign
0.16
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.025
D
MutationAssessor
Benign
2.0
M;.;.;.;.;.;.
MutationTaster
Benign
0.98
D;D;D;D;D;D;D
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.1
N;N;N;N;N;N;N
REVEL
Benign
0.27
Sift
Uncertain
0.015
D;D;D;D;D;D;D
Sift4G
Benign
0.18
T;T;T;T;T;T;T
Polyphen
0.0060
B;.;.;B;B;.;B
Vest4
0.24
MutPred
0.23
Gain of phosphorylation at N1348 (P = 0.002);.;.;.;.;.;.;
MVP
0.77
MPC
0.079
ClinPred
0.42
T
GERP RS
3.7
Varity_R
0.11
gMVP
0.31

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: rs371943557; hg19: chr9-98209495; API