rs145196322

Variant names:

• chr9-95459700-G-A
• rs145196322
• NM_000264.5:c.2787C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95459700-G-A
• chr9-95459700-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000264.5(PTCH1):​c.2787C>T​(p.Asn929Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.908
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-95459700-G-A is Benign according to our data. Variant chr9-95459700-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.908 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000591 (90/152312) while in subpopulation NFE AF = 0.00118 (80/68024). AF 95% confidence interval is 0.000968. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 90 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.2787C>T	p.Asn929Asn	synonymous	Exon 17 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.2784C>T	p.Asn928Asn	synonymous	Exon 17 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.2631C>T	p.Asn877Asn	synonymous	Exon 16 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.2787C>T	p.Asn929Asn	synonymous	Exon 17 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2784C>T	p.Asn928Asn	synonymous	Exon 17 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.2334C>T	p.Asn778Asn	synonymous	Exon 17 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000577 AC: 145 AN: 251480 AF XY: 0.000559

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00109 AC: 1594 AN: 1461866 Hom.: 1 Cov.: 32 AF XY: 0.00106 AC XY: 773 AN XY: 727234

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00137 AC: 1524 AN: 1112002

Other (OTH) AF: 0.000646 AC: 39 AN: 60392

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74492

African (AFR) AF: 0.000120 AC: 5 AN: 41576

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000932 Hom.: 0

Bravo AF: 0.000578

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Gorlin syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Holoprosencephaly 7 (1)
-	-	1	Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1;CN376810:Basal cell nevus syndrome 1 (1)
-	-	1	not specified (1)
-	-	1	PTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.75
DANN	Benign	0.56
PhyloP100		-0.91
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs145196322; hg19: chr9-98221982; COSMIC: COSV59471149;