9-95449037-A-G

Variant names:

• chr9-95449037-A-G
• rs199982439
• NM_000264.5:c.3804+32T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.3804+32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,612,168 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (8 hom.)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00900
• 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, Labcorp Genetics (formerly Invitae), Orphanet
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-95449037-A-G is Benign according to our data. Variant chr9-95449037-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00233 (354/152086) while in subpopulation NFE AF = 0.00281 (191/67986). AF 95% confidence interval is 0.00248. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 354 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.3804+32T>C		intron	N/A	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3801+32T>C		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.3648+32T>C		intron	N/A	NP_001341847.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.3804+32T>C		intron	N/A	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3801+32T>C		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.3351+32T>C		intron	N/A	ENSP00000414823.2

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 151968 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00303 AC: 751 AN: 247796 AF XY: 0.00314

Gnomad AFR exome AF: 0.000445

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00270

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00428

GnomAD4 exome AF: 0.00277 AC: 4049 AN: 1460082 Hom.: 8 Cov.: 31 AF XY: 0.00284 AC XY: 2065 AN XY: 725936

African (AFR) AF: 0.000329 AC: 11 AN: 33460

American (AMR) AF: 0.00224 AC: 100 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 454 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86230

European-Finnish (FIN) AF: 0.00238 AC: 127 AN: 53270

Middle Eastern (MID) AF: 0.00885 AC: 51 AN: 5760

European-Non Finnish (NFE) AF: 0.00276 AC: 3064 AN: 1110588

Other (OTH) AF: 0.00345 AC: 208 AN: 60310

GnomAD4 genome AF: 0.00233 AC: 354 AN: 152086 Hom.: 2 Cov.: 33 AF XY: 0.00226 AC XY: 168 AN XY: 74338

African (AFR) AF: 0.000482 AC: 20 AN: 41482

American (AMR) AF: 0.00223 AC: 34 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4804

European-Finnish (FIN) AF: 0.00227 AC: 24 AN: 10576

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 67986

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00427 Hom.: 0

Bravo AF: 0.00229

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gorlin syndrome Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.70
PhyloP100		0.0090
Mutation Taster		=100/0	polymorphism

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: rs199982439; hg19: chr9-98211319;