9-95444104-GTTTT-GTTT

Variant names:

• chr9-95444104-GT-G
• rs548096592
• NM_000264.5:c.*2288delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000264.5(PTCH1):​c.*2288delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 145,738 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.018 (0 hom.)
• Consequence: PTCH1 NM_000264.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.653
• Publications: 0 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, Orphanet, Labcorp Genetics (formerly Invitae)
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (321/145406) while in subpopulation AFR AF = 0.006 (240/39990). AF 95% confidence interval is 0.00538. There are 0 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 321 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.*2288delA		3_prime_UTR	Exon 24 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.*2288delA		3_prime_UTR	Exon 24 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.*2288delA		3_prime_UTR	Exon 23 of 23	NP_001341847.1	A0A1W5YLI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.*2288delA		3_prime_UTR	Exon 24 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.*2288delA		3_prime_UTR	Exon 24 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000430669.6	TSL:5	c.*2807delA		3_prime_UTR	Exon 23 of 23	ENSP00000410287.2	Q13635-3

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 321 AN: 145356 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00602

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000686

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00304

Gnomad FIN AF: 0.000907

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000699

Gnomad OTH AF: 0.00101

GnomAD4 exome AF: 0.0181 AC: 6 AN: 332 Hom.: 0 Cov.: 0 AF XY: 0.0101 AC XY: 2 AN XY: 198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0182 AC: 6 AN: 330

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000505657), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00221 AC: 321 AN: 145406 Hom.: 0 Cov.: 32 AF XY: 0.00221 AC XY: 156 AN XY: 70626

African (AFR) AF: 0.00600 AC: 240 AN: 39990

American (AMR) AF: 0.000685 AC: 10 AN: 14600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5028

South Asian (SAS) AF: 0.00305 AC: 14 AN: 4590

European-Finnish (FIN) AF: 0.000907 AC: 8 AN: 8816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000699 AC: 46 AN: 65842

Other (OTH) AF: 0.00101 AC: 2 AN: 1990

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00212

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

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: rs548096592; hg19: chr9-98206386;