9-95504088-A-G

Variant names:

• chr9-95504088-A-G
• rs4448343
• NM_000264.5:c.394+2319T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.394+2319T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00077 (7 hom., cov: 0)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269
• Publications: 31 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000775 (45/58088) while in subpopulation AFR AF = 0.00197 (20/10164). AF 95% confidence interval is 0.0013. There are 7 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.394+2319T>C		intron_variant	Intron 2 of 23	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.391+2319T>C		intron_variant	Intron 2 of 23	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.394+2319T>C		intron_variant	Intron 2 of 23	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.391+2319T>C		intron_variant	Intron 2 of 23	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 45 AN: 58080 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000122

Gnomad ASJ AF: 0.00143

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000454

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.000775 AC: 45 AN: 58088 Hom.: 7 Cov.: 0 AF XY: 0.000633 AC XY: 18 AN XY: 28438

African (AFR) AF: 0.00197 AC: 20 AN: 10164

American (AMR) AF: 0.000122 AC: 1 AN: 8198

Ashkenazi Jewish (ASJ) AF: 0.00143 AC: 2 AN: 1396

East Asian (EAS) AF: 0.00 AC: 0 AN: 2198

South Asian (SAS) AF: 0.00112 AC: 3 AN: 2670

European-Finnish (FIN) AF: 0.00182 AC: 6 AN: 3304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.000454 AC: 13 AN: 28640

Other (OTH) AF: 0.00 AC: 0 AN: 896

Alfa AF: 0.335 Hom.: 28963

Bravo AF: 0.365

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.42
PhyloP100		0.27
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: rs4448343; hg19: chr9-98266370;