chr9-95476121-G-A

Variant names:

• chr9-95476121-G-A
• rs2066830
• NM_000264.5:c.1641C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000264.5(PTCH1):​c.1641C>T​(p.Ser547Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,613,520 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (116 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.910
• Publications: 11 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 9-95476121-G-A is Benign according to our data. Variant chr9-95476121-G-A is described in ClinVar as Benign. ClinVar VariationId is 132700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00784 (1194/152322) while in subpopulation NFE AF = 0.0128 (870/68026). AF 95% confidence interval is 0.0121. There are 9 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1194 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.1641C>T	p.Ser547Ser	synonymous	Exon 12 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.1638C>T	p.Ser546Ser	synonymous	Exon 12 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.1485C>T	p.Ser495Ser	synonymous	Exon 11 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.1641C>T	p.Ser547Ser	synonymous	Exon 12 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.1638C>T	p.Ser546Ser	synonymous	Exon 12 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.1188C>T	p.Ser396Ser	synonymous	Exon 12 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1194 AN: 152204 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00784 AC: 1957 AN: 249624 AF XY: 0.00797

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.00771

GnomAD4 exome AF: 0.0116 AC: 16959 AN: 1461198 Hom.: 116 Cov.: 34 AF XY: 0.0111 AC XY: 8103 AN XY: 726872

African (AFR) AF: 0.00194 AC: 65 AN: 33466

American (AMR) AF: 0.00269 AC: 120 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86112

European-Finnish (FIN) AF: 0.0109 AC: 579 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0141 AC: 15662 AN: 1111754

Other (OTH) AF: 0.00830 AC: 501 AN: 60364

GnomAD4 genome AF: 0.00784 AC: 1194 AN: 152322 Hom.: 9 Cov.: 32 AF XY: 0.00771 AC XY: 574 AN XY: 74484

African (AFR) AF: 0.00272 AC: 113 AN: 41568

American (AMR) AF: 0.00490 AC: 75 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0128 AC: 870 AN: 68026

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00975 Hom.: 2

Bravo AF: 0.00727

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0112

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.8
DANN	Benign	0.88
PhyloP100		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs2066830; hg19: chr9-98238403; COSMIC: COSV59461249; COSMIC: COSV59461249;