rs1554700016

Positions:

• chr9-95480580-G-A
• chr9-95480580-G-C
• chr9-95480580-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000264.5(PTCH1):​c.755C>T​(p.Pro252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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=0.4050731).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.755C>T	p.Pro252Leu	missense_variant	6/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.752C>T	p.Pro251Leu	missense_variant	6/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.755C>T	p.Pro252Leu	missense_variant	6/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.752C>T	p.Pro251Leu	missense_variant	6/24	5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461538 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727116

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D;.;D;D;.;.;D;.;.;.;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.7	L;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.029	B;.;.;B;B;.;P;.;.;.;.
Vest4		0.74
MutPred		0.57		Loss of sheet (P = 0.0104);.;.;.;.;.;.;.;.;.;.;
MVP		0.51
MPC		0.57
ClinPred		0.80	D
GERP RS		5.9
Varity_R		0.36
gMVP		0.61

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: chr9-98242862;