rs543169448

chr9-95506370-G-Achr9-95506370-G-Cchr9-95506370-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000264.5(PTCH1):c.394+37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,600,772 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.107

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000126 (182/1448798) while in subpopulation SAS AF= 0.00195 (166/85006). AF 95% confidence interval is 0.00171. There are 0 homozygotes in gnomad4_exome. There are 133 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.394+37C>T		intron_variant		ENST00000331920.11
PTCH1	NM_001083603.3	c.391+37C>T		intron_variant		ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.394+37C>T		intron_variant		5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.391+37C>T		intron_variant		5	NM_001083603.3
	ENST00000604104.1	n.136G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151858 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000291 AC: 68 AN: 233442 Hom.: 0 AF XY: 0.000402 AC XY: 51 AN XY: 126924

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000580

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000962

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 182 AN: 1448798 Hom.: 0 Cov.: 30 AF XY: 0.000185 AC XY: 133 AN XY: 720376

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000459

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000543

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151974 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74288

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.5
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs543169448; hg19: chr9-98268652;