9-95444104-G-GT

Position:

• chr9-95444104-G-GT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_000264.5(PTCH1):​c.*2288dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.037 in 145,418 control chromosomes in the GnomAD database, including 205 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (205 hom., cov: 32)
  • Exomes 𝑓: 0.079 (0 hom.)
• Consequence: PTCH1 NM_000264.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.653

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0963 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.*2288dupA		3_prime_UTR_variant	24/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.*2288dupA		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.*2288dupA		3_prime_UTR_variant	24/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951	c.*2288dupA		3_prime_UTR_variant	24/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5341 AN: 145070 Hom.: 205 Cov.: 32

Gnomad AFR AF: 0.0989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0645

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.00891

Gnomad MID AF: 0.0235

Gnomad NFE AF: 0.00705

Gnomad OTH AF: 0.0242

GnomAD4 exome AF: 0.0795 AC: 24 AN: 302 Hom.: 0 Cov.: 0 AF XY: 0.0824 AC XY: 15 AN XY: 182

Gnomad4 FIN exome AF: 0.0767

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.0369 AC: 5354 AN: 145116 Hom.: 205 Cov.: 32 AF XY: 0.0367 AC XY: 2585 AN XY: 70466

Gnomad4 AFR AF: 0.0989

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.0647

Gnomad4 SAS AF: 0.0399

Gnomad4 FIN AF: 0.00891

Gnomad4 NFE AF: 0.00706

Gnomad4 OTH AF: 0.0241

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly sequence Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs548096592; hg19: chr9-98206386;