rs144501989

Variant names:

• chr9-95468831-C-A
• rs144501989
• NM_000264.5:c.2170G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95468831-C-A
• chr9-95468831-C-G
• chr9-95468831-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000264.5(PTCH1):​c.2170G>T​(p.Glu724*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.59
• Publications: 1 publications found

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]

PTCH1 Gene-Disease associations (from GenCC):

• basal cell nevus syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

LOC100507346 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95468831-C-A is Pathogenic according to our data. Variant chr9-95468831-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4056127.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.2170G>T	p.Glu724*	stop_gained	Exon 14 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.2167G>T	p.Glu723*	stop_gained	Exon 14 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.2170G>T	p.Glu724*	stop_gained	Exon 14 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.2167G>T	p.Glu723*	stop_gained	Exon 14 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Basal cell nevus syndrome 1 Pathogenic:1

Jun 17, 2025

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTCH1 c.2170G>T p.(Glu724Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in at least one individual with nevoid basal cell carcinoma syndrome (PMID: 29575684, 31374299). It has also been identified in an individual with SHH-medulloblastoma (internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		4.6
Vest4		0.98
GERP RS		4.8
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144501989; hg19: chr9-98231113;