9-95508351-G-C

Variant names:

• chr9-95508351-G-C
• rs540045689
• NM_000264.5:c.11C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_000264.5(PTCH1):​c.11C>G​(p.Ala4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,212,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.15
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1459006).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000413 (44/1064888) while in subpopulation EAS AF = 0.00177 (44/24882). AF 95% confidence interval is 0.00135. There are 0 homozygotes in GnomAdExome4. There are 20 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 44 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.11C>G	p.Ala4Gly	missense	Exon 1 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1752C>G		intron	N/A	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.11C>G	p.Ala4Gly	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.11C>G	p.Ala4Gly	missense	Exon 1 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1752C>G		intron	N/A	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1752C>G		intron	N/A	ENSP00000449745.1	A0A0C4DGJ5

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147964 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: 0.000200

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000413 AC: 44 AN: 1064888 Hom.: 0 Cov.: 33 AF XY: 0.0000395 AC XY: 20 AN XY: 506014

African (AFR) AF: 0.00 AC: 0 AN: 21884

American (AMR) AF: 0.00 AC: 0 AN: 7632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13180

East Asian (EAS) AF: 0.00177 AC: 44 AN: 24882

South Asian (SAS) AF: 0.00 AC: 0 AN: 20126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2798

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 909758

Other (OTH) AF: 0.00 AC: 0 AN: 42118

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148072 Hom.: 0 Cov.: 32 AF XY: 0.0000277 AC XY: 2 AN XY: 72272

African (AFR) AF: 0.00 AC: 0 AN: 40384

American (AMR) AF: 0.00 AC: 0 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4986

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66714

Other (OTH) AF: 0.00 AC: 0 AN: 2046

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Gorlin syndrome (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Holoprosencephaly 7 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0075	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.053	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.57
MPC		0.86
ClinPred		0.50	T
GERP RS		2.0
PromoterAI		-0.020	Neutral
Varity_R		0.26
gMVP		0.64
Mutation Taster		=77/23	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: rs540045689; hg19: chr9-98270633;