9-95508253-C-G

Variant names:

• chr9-95508253-C-G
• rs199976372
• NM_000264.5:c.109G>C

Variant summary

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

The ENST00000331920.11(PTCH1):​c.109G>C​(p.Gly37Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000743 in 1,600,892 control chromosomes in the GnomAD database, including 9 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 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. G37A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (6 hom.)
• Consequence: PTCH1 ENST00000331920.11 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.80
• Publications: 9 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, Labcorp Genetics (formerly Invitae), Orphanet
• 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=0.005396843).
• BP6: Variant 9-95508253-C-G is Benign according to our data. Variant chr9-95508253-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 237450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00109 (165/151816) while in subpopulation EAS AF = 0.0156 (80/5142). AF 95% confidence interval is 0.0128. There are 3 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 165 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000331920.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.109G>C	p.Gly37Arg	missense	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1654G>C		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.109G>C	p.Gly37Arg	missense	Exon 1 of 23	NP_001341847.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.109G>C	p.Gly37Arg	missense	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1654G>C		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1654G>C		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 151704 Hom.: 3 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: 0.0153

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00333

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000664

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00143 AC: 322 AN: 225954 AF XY: 0.00144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0127

Gnomad FIN exome AF: 0.00329

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.000896

GnomAD4 exome AF: 0.000707 AC: 1025 AN: 1449076 Hom.: 6 Cov.: 34 AF XY: 0.000711 AC XY: 512 AN XY: 720324

African (AFR) AF: 0.0000302 AC: 1 AN: 33068

American (AMR) AF: 0.0000227 AC: 1 AN: 44094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.0120 AC: 468 AN: 39106

South Asian (SAS) AF: 0.000516 AC: 44 AN: 85294

European-Finnish (FIN) AF: 0.00291 AC: 143 AN: 49202

Middle Eastern (MID) AF: 0.000636 AC: 3 AN: 4720

European-Non Finnish (NFE) AF: 0.000273 AC: 302 AN: 1107966

Other (OTH) AF: 0.00106 AC: 63 AN: 59696

GnomAD4 genome AF: 0.00109 AC: 165 AN: 151816 Hom.: 3 Cov.: 32 AF XY: 0.00151 AC XY: 112 AN XY: 74190

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.0156 AC: 80 AN: 5142

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00333 AC: 35 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000664 AC: 45 AN: 67756

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000748

ExAC AF: 0.00131 AC: 155

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Gorlin syndrome (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Holoprosencephaly 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.74
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.41	N
PhyloP100		4.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.40	N
REVEL	Benign	0.25
Sift	Benign	0.22	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.17		Gain of helix (P = 0.027)
MVP		0.37
MPC		1.6
ClinPred		0.028	T
GERP RS		3.7
PromoterAI		-0.050	Neutral
Varity_R		0.062
gMVP		0.56
Mutation Taster		=82/18	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: rs199976372; hg19: chr9-98270535; COSMIC: COSV59466417; COSMIC: COSV59466417;