rs1060502284

Variant names:

• chr9-95506472-C-G
• rs1060502284
• NM_000264.5:c.329G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-95506472-C-G
• chr9-95506472-C-A
• chr9-95506472-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000264.5(PTCH1):​c.329G>C​(p.Gly110Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G110R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 7.29
• Publications: 0 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

ENSG00000271155 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 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.329G>C	p.Gly110Ala	missense	Exon 2 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.326G>C	p.Gly109Ala	missense	Exon 2 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.329G>C	p.Gly110Ala	missense	Exon 2 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.329G>C	p.Gly110Ala	missense	Exon 2 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.326G>C	p.Gly109Ala	missense	Exon 2 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000468211.6	TSL:1	c.131G>C	p.Gly44Ala	missense	Exon 2 of 5	ENSP00000449745.1	A0A0C4DGJ5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250710 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461324 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726954

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111766

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Gorlin syndrome (2)
-	1	-	Basal cell carcinoma, susceptibility to, 1 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.56
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.070	B
Vest4		0.81
MutPred		0.47		Loss of sheet (P = 0.0817)
MVP		0.78
MPC		0.60
ClinPred		0.90	D
GERP RS		4.5
PromoterAI		0.031	Neutral
Varity_R		0.71
gMVP		0.65
Mutation Taster		=16/84	disease causing

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: rs1060502284; hg19: chr9-98268754;