rs2227968

Variant names:

• chr9-95447411-G-A
• rs2227968
• NM_000264.5:c.3845C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95447411-G-A
• chr9-95447411-G-C
• chr9-95447411-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.3845C>T​(p.Pro1282Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00165 in 1,605,002 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P1282R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0088 (25 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (26 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 5.19
• Publications: 12 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=0.0031888783).
• BP6: Variant 9-95447411-G-A is Benign according to our data. Variant chr9-95447411-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00877 (1336/152294) while in subpopulation AFR AF = 0.0302 (1256/41558). AF 95% confidence interval is 0.0288. There are 25 homozygotes in GnomAd4. There are 650 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1336 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.3845C>T	p.Pro1282Leu	missense	Exon 23 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3842C>T	p.Pro1281Leu	missense	Exon 23 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.3689C>T	p.Pro1230Leu	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.3845C>T	p.Pro1282Leu	missense	Exon 23 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3842C>T	p.Pro1281Leu	missense	Exon 23 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.3392C>T	p.Pro1131Leu	missense	Exon 23 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152176 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00224 AC: 541 AN: 241766 AF XY: 0.00178

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000546

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000905 AC: 1315 AN: 1452708 Hom.: 26 Cov.: 33 AF XY: 0.000803 AC XY: 580 AN XY: 722064

African (AFR) AF: 0.0291 AC: 962 AN: 33096

American (AMR) AF: 0.00185 AC: 81 AN: 43770

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 34 AN: 25710

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39594

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85722

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51138

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5692

European-Non Finnish (NFE) AF: 0.0000903 AC: 100 AN: 1108016

Other (OTH) AF: 0.00195 AC: 117 AN: 59970

GnomAD4 genome AF: 0.00877 AC: 1336 AN: 152294 Hom.: 25 Cov.: 33 AF XY: 0.00873 AC XY: 650 AN XY: 74474

African (AFR) AF: 0.0302 AC: 1256 AN: 41558

American (AMR) AF: 0.00301 AC: 46 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00322 Hom.: 14

Bravo AF: 0.00963

ESP6500AA AF: 0.0239 AC: 103

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.00265 AC: 321

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	-	5	not provided (5)
-	-	3	Gorlin syndrome (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Holoprosencephaly 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.23
Sift	Benign	0.068	T
Sift4G	Benign	0.27	T
Polyphen		0.38	B
Vest4		0.49
MVP		0.57
MPC		0.083
ClinPred		0.012	T
GERP RS		2.9
Varity_R		0.074
gMVP		0.29
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: rs2227968; hg19: chr9-98209693;