rs1554700574

Variant names:

• chr9-95481947-ACAGGAGG-A
• rs1554700574
• ENST00000468211.6:c.543_549delCCTCCTG

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.741_746+1delCCTCCTG​(p.Tyr247_Leu249delinsTer) variant causes a stop gained, splice donor, disruptive inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 stop_gained, splice_donor, disruptive_inframe_deletion, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.95
• Publications: 0 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, Orphanet, Labcorp Genetics (formerly Invitae)
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

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 9-95481947-ACAGGAGG-A is Pathogenic according to our data. Variant chr9-95481947-ACAGGAGG-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 524565.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.741_746+1delCCTCCTG	p.Tyr247_Leu249delinsTer	stop_gained splice_donor disruptive_inframe_deletion splice_region intron	Exon 5 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.738_743+1delCCTCCTG	p.Tyr246_Leu248delinsTer	stop_gained splice_donor disruptive_inframe_deletion splice_region intron	Exon 5 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354919.2		c.543_549delCCTCCTG	p.Leu182LysfsTer19	frameshift	Exon 5 of 5	NP_001341848.1	A0A0C4DGJ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000468211.6	TSL:1	c.543_549delCCTCCTG	p.Leu182LysfsTer19	frameshift	Exon 5 of 5	ENSP00000449745.1	A0A0C4DGJ5
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.741_746+1delCCTCCTG	p.Tyr247_Leu249delinsTer	stop_gained splice_donor disruptive_inframe_deletion splice_region intron	Exon 5 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.738_743+1delCCTCCTG	p.Tyr246_Leu248delinsTer	stop_gained splice_donor disruptive_inframe_deletion splice_region intron	Exon 5 of 24	ENSP00000389744.2	Q13635-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Gorlin syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

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

Other links and lift over

dbSNP: rs1554700574; hg19: chr9-98244229;