NM_000264.5:c.3583A>T

Variant names:

• chr9-95449290-T-A
• rs2236405
• NM_000264.5:c.3583A>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.3583A>T​(p.Thr1195Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0223 in 1,557,458 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1195I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.047 (348 hom., cov: 33)
  • Exomes 𝑓: 0.020 (826 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 4.02
• Publications: 44 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=0.0019354224).
• BP6: Variant 9-95449290-T-A is Benign according to our data. Variant chr9-95449290-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 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.3583A>T	p.Thr1195Ser	missense	Exon 22 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3580A>T	p.Thr1194Ser	missense	Exon 22 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.3427A>T	p.Thr1143Ser	missense	Exon 21 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.3583A>T	p.Thr1195Ser	missense	Exon 22 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3580A>T	p.Thr1194Ser	missense	Exon 22 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.3130A>T	p.Thr1044Ser	missense	Exon 22 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7130 AN: 152148 Hom.: 347 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0340 AC: 5516 AN: 162192 AF XY: 0.0339

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0425

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.00844

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0197 AC: 27632 AN: 1405192 Hom.: 826 Cov.: 31 AF XY: 0.0202 AC XY: 14008 AN XY: 693950

African (AFR) AF: 0.122 AC: 3913 AN: 32198

American (AMR) AF: 0.0137 AC: 493 AN: 36066

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 1112 AN: 25224

East Asian (EAS) AF: 0.127 AC: 4645 AN: 36664

South Asian (SAS) AF: 0.0472 AC: 3778 AN: 80048

European-Finnish (FIN) AF: 0.00728 AC: 348 AN: 47778

Middle Eastern (MID) AF: 0.0273 AC: 156 AN: 5704

European-Non Finnish (NFE) AF: 0.0106 AC: 11510 AN: 1083148

Other (OTH) AF: 0.0287 AC: 1677 AN: 58362

GnomAD4 genome AF: 0.0469 AC: 7148 AN: 152266 Hom.: 348 Cov.: 33 AF XY: 0.0478 AC XY: 3558 AN XY: 74478

African (AFR) AF: 0.116 AC: 4812 AN: 41546

American (AMR) AF: 0.0213 AC: 326 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3472

East Asian (EAS) AF: 0.134 AC: 693 AN: 5168

South Asian (SAS) AF: 0.0539 AC: 260 AN: 4824

European-Finnish (FIN) AF: 0.00668 AC: 71 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 766 AN: 68010

Other (OTH) AF: 0.0321 AC: 68 AN: 2116

Alfa AF: 0.0218 Hom.: 67

Bravo AF: 0.0509

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.0976 AC: 426

ESP6500EA AF: 0.0131 AC: 111

ExAC AF: 0.0243 AC: 2734

Asia WGS AF: 0.0810 AC: 281 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (6)
-	-	3	Gorlin syndrome (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.043
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.43
Sift	Benign	0.086	T
Sift4G	Benign	0.24	T
Polyphen		0.47	P
Vest4		0.25
MPC		0.60
ClinPred		0.016	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.56
Mutation Taster		=96/4	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: rs2236405; hg19: chr9-98211572; COSMIC: COSV59467963;