chr9-95444117-T-A

Position:

• chr9-95444117-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000264.5(PTCH1):​c.*2276A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 151,558 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTCH1 NM_000264.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.434

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-95444117-T-A is Benign according to our data. Variant chr9-95444117-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 367627.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00612 (928/151558) while in subpopulation AFR AF= 0.0101 (416/41192). AF 95% confidence interval is 0.0093. There are 7 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 928 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.*2276A>T		3_prime_UTR_variant	24/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.*2276A>T		3_prime_UTR_variant	24/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920	c.*2276A>T		3_prime_UTR_variant	24/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951	c.*2276A>T		3_prime_UTR_variant	24/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 930 AN: 151442 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00520

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.000856

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00461

Gnomad OTH AF: 0.00770

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 398 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 240

Gnomad4 FIN exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00612 AC: 928 AN: 151558 Hom.: 7 Cov.: 32 AF XY: 0.00549 AC XY: 407 AN XY: 74074

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.00519

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00354

Gnomad4 FIN AF: 0.000856

Gnomad4 NFE AF: 0.00461

Gnomad4 OTH AF: 0.00762

Alfa AF: 0.00600 Hom.: 0

Bravo AF: 0.00723

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Holoprosencephaly 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

PTCH1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.2
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs868749157; hg19: chr9-98206399; COSMIC: COSV59468240; COSMIC: COSV59468240;