rs118174136

Variant names:

• chr9-95443236-C-T
• rs118174136
• NM_000264.5:c.*3157G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000264.5(PTCH1):​c.*3157G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00702 in 152,256 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTCH1 NM_000264.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.30
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• nevoid basal cell carcinoma syndrome

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

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-95443236-C-T is Benign according to our data. Variant chr9-95443236-C-T is described in ClinVar as Benign. ClinVar VariationId is 367621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00702 (1069/152256) while in subpopulation EAS AF = 0.0295 (153/5182). AF 95% confidence interval is 0.0257. There are 8 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1069 AD gene.

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.*3157G>A		3_prime_UTR	Exon 24 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.*3157G>A		3_prime_UTR	Exon 24 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.*3157G>A		3_prime_UTR	Exon 23 of 23	NP_001341847.1	A0A1W5YLI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.*3157G>A		3_prime_UTR	Exon 24 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.*3157G>A		3_prime_UTR	Exon 24 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000711046.1		c.*3157G>A		3_prime_UTR	Exon 24 of 24	ENSP00000518556.1	Q13635-3

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1052 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00831

Gnomad OTH AF: 0.00574

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00702 AC: 1069 AN: 152256 Hom.: 8 Cov.: 32 AF XY: 0.00774 AC XY: 576 AN XY: 74450

African (AFR) AF: 0.00180 AC: 75 AN: 41554

American (AMR) AF: 0.00177 AC: 27 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.0295 AC: 153 AN: 5182

South Asian (SAS) AF: 0.0187 AC: 90 AN: 4814

European-Finnish (FIN) AF: 0.0109 AC: 116 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00832 AC: 566 AN: 68020

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00632 Hom.: 5

Bravo AF: 0.00594

Asia WGS AF: 0.0510 AC: 177 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Gorlin syndrome (1)
-	-	1	Holoprosencephaly 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.32
DANN	Benign	0.54
PhyloP100		-1.3

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

Other links and lift over

dbSNP: rs118174136; hg19: chr9-98205518;