rs357564

Variant names:

• chr9-95447312-G-A
• rs357564
• NM_000264.5:c.3944C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95447312-G-A
• chr9-95447312-G-C
• chr9-95447312-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000264.5(PTCH1):​c.3944C>T​(p.Pro1315Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,612,980 control chromosomes in the GnomAD database, including 103,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1315S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.33 (8748 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95236 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 9.54
• Publications: 118 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032435358).
• BP6: Variant 9-95447312-G-A is Benign according to our data. Variant chr9-95447312-G-A is described in ClinVar as Benign. ClinVar VariationId is 41663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

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.3944C>T	p.Pro1315Leu	missense	Exon 23 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3941C>T	p.Pro1314Leu	missense	Exon 23 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.3788C>T	p.Pro1263Leu	missense	Exon 22 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.3944C>T	p.Pro1315Leu	missense	Exon 23 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3941C>T	p.Pro1314Leu	missense	Exon 23 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.3491C>T	p.Pro1164Leu	missense	Exon 23 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50147 AN: 151954 Hom.: 8752 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.338

GnomAD2 exomes AF: 0.389 AC: 95817 AN: 246178 AF XY: 0.388

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.563

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.356 AC: 519565 AN: 1460908 Hom.: 95236 Cov.: 70 AF XY: 0.358 AC XY: 259922 AN XY: 726768

African (AFR) AF: 0.230 AC: 7694 AN: 33480

American (AMR) AF: 0.476 AC: 21269 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 8227 AN: 26136

East Asian (EAS) AF: 0.583 AC: 23162 AN: 39700

South Asian (SAS) AF: 0.451 AC: 38914 AN: 86258

European-Finnish (FIN) AF: 0.409 AC: 21494 AN: 52518

Middle Eastern (MID) AF: 0.316 AC: 1820 AN: 5762

European-Non Finnish (NFE) AF: 0.338 AC: 375366 AN: 1111956

Other (OTH) AF: 0.358 AC: 21619 AN: 60374

GnomAD4 genome AF: 0.330 AC: 50158 AN: 152072 Hom.: 8748 Cov.: 32 AF XY: 0.338 AC XY: 25139 AN XY: 74320

African (AFR) AF: 0.232 AC: 9637 AN: 41524

American (AMR) AF: 0.387 AC: 5922 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1115 AN: 3472

East Asian (EAS) AF: 0.563 AC: 2879 AN: 5112

South Asian (SAS) AF: 0.472 AC: 2271 AN: 4814

European-Finnish (FIN) AF: 0.399 AC: 4234 AN: 10608

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22872 AN: 67946

Other (OTH) AF: 0.337 AC: 712 AN: 2110

Alfa AF: 0.337 Hom.: 35320

Bravo AF: 0.326

TwinsUK AF: 0.328 AC: 1215

ALSPAC AF: 0.340 AC: 1309

ESP6500AA AF: 0.239 AC: 1009

ESP6500EA AF: 0.330 AC: 2752

ExAC AF: 0.380 AC: 45697

Asia WGS AF: 0.486 AC: 1685 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.332

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (6)
-	-	4	Gorlin syndrome (4)
-	-	2	Holoprosencephaly 7 (2)
-	-	1	Basal cell nevus syndrome 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.023	D
Polyphen		0.91	P
Vest4		0.57
MPC		0.40
ClinPred		0.027	T
GERP RS		4.8
Varity_R		0.21
gMVP		0.55
Mutation Taster		=98/2	polymorphism (auto)

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: rs357564; hg19: chr9-98209594; COSMIC: COSV59463357;