rs756724967

Variant names:

• chr9-95508301-T-C
• rs756724967
• NM_000264.5:c.61A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-95508301-T-C
• chr9-95508301-T-G
• chr9-95508301-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000264.5(PTCH1):​c.61A>G​(p.Ile21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,440,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I21M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08370191).

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.61A>G	p.Ile21Val	missense	Exon 1 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1702A>G		intron	N/A	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.61A>G	p.Ile21Val	missense	Exon 1 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.61A>G	p.Ile21Val	missense	Exon 1 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1702A>G		intron	N/A	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1702A>G		intron	N/A	ENSP00000449745.1	A0A0C4DGJ5

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151008 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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000310 AC: 4 AN: 1289192 Hom.: 0 Cov.: 33 AF XY: 0.00000158 AC XY: 1 AN XY: 631844

African (AFR) AF: 0.00 AC: 0 AN: 25718

American (AMR) AF: 0.00 AC: 0 AN: 19420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19738

East Asian (EAS) AF: 0.00 AC: 0 AN: 30218

South Asian (SAS) AF: 0.00 AC: 0 AN: 63618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3718

European-Non Finnish (NFE) AF: 0.00000386 AC: 4 AN: 1035042

Other (OTH) AF: 0.00 AC: 0 AN: 52928

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151008 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73706

African (AFR) AF: 0.00 AC: 0 AN: 41252

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10332

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67572

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Gorlin syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.34
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.20
Sift	Benign	0.72	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.15		Gain of MoRF binding (P = 0.1157)
MVP		0.19
MPC		0.45
ClinPred		0.033	T
GERP RS		1.3
PromoterAI		-0.0091	Neutral
Varity_R		0.051
gMVP		0.25
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756724967; hg19: chr9-98270583;