9-95449242-G-T

Variant names:

• chr9-95449242-G-T
• NM_000264.5:c.3631C>A

Variant summary

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

The NM_000264.5(PTCH1):​c.3631C>A​(p.Pro1211Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,429,032 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: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31212538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3631C>A	p.Pro1211Thr	missense_variant	Exon 22 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3628C>A	p.Pro1210Thr	missense_variant	Exon 22 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.3631C>A	p.Pro1211Thr	missense_variant	Exon 22 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3628C>A	p.Pro1210Thr	missense_variant	Exon 22 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429032 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707712

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: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.;.;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;.;D;D;.;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.081	T;T;T;T;T;T;T
Sift4G	Benign	0.076	T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;D;D;.;D
Vest4		0.53
MutPred		0.20		Loss of catalytic residue at P1210 (P = 0.016);.;.;.;.;.;.;
MVP		0.54
MPC		0.11
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.12
gMVP		0.68

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: chr9-98211524;