9-95477838-G-A

Variant names:

• chr9-95477838-G-A
• rs2297086
• NM_000264.5:c.1348-136C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000264.5(PTCH1):​c.1348-136C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,442,582 control chromosomes in the GnomAD database, including 100,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (16099 hom., cov: 33)
  • Exomes 𝑓: 0.35 (84529 hom.)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.363
• Publications: 9 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=-0.88).
• BP6: Variant 9-95477838-G-A is Benign according to our data. Variant chr9-95477838-G-A is described in ClinVar as Benign. ClinVar VariationId is 677044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

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.1348-136C>T		intron	N/A	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.1345-136C>T		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.1347+217C>T		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.1348-136C>T		intron	N/A	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.1345-136C>T		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.895-136C>T		intron	N/A	ENSP00000414823.2

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65958 AN: 151962 Hom.: 16042 Cov.: 33

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.389

GnomAD4 exome AF: 0.355 AC: 457572 AN: 1290502 Hom.: 84529 AF XY: 0.352 AC XY: 225598 AN XY: 640532

African (AFR) AF: 0.668 AC: 19307 AN: 28904

American (AMR) AF: 0.201 AC: 7013 AN: 34878

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 9936 AN: 24018

East Asian (EAS) AF: 0.319 AC: 11206 AN: 35178

South Asian (SAS) AF: 0.263 AC: 19809 AN: 75448

European-Finnish (FIN) AF: 0.373 AC: 18177 AN: 48674

Middle Eastern (MID) AF: 0.353 AC: 1663 AN: 4706

European-Non Finnish (NFE) AF: 0.357 AC: 351024 AN: 984474

Other (OTH) AF: 0.358 AC: 19437 AN: 54222

GnomAD4 genome AF: 0.434 AC: 66078 AN: 152080 Hom.: 16099 Cov.: 33 AF XY: 0.428 AC XY: 31785 AN XY: 74328

African (AFR) AF: 0.660 AC: 27381 AN: 41466

American (AMR) AF: 0.262 AC: 4006 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1425 AN: 3470

East Asian (EAS) AF: 0.343 AC: 1772 AN: 5168

South Asian (SAS) AF: 0.253 AC: 1219 AN: 4816

European-Finnish (FIN) AF: 0.378 AC: 3997 AN: 10574

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24966 AN: 67986

Other (OTH) AF: 0.394 AC: 831 AN: 2108

Alfa AF: 0.388 Hom.: 34838

Bravo AF: 0.436

Asia WGS AF: 0.326 AC: 1134 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.65
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2297086; hg19: chr9-98240120; COSMIC: COSV59499920; COSMIC: COSV59499920;