rs199476092

Variant names:

• chr9-95467197-T-C
• rs199476092
• NM_000264.5:c.2479A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-95467197-T-C
• chr9-95467197-T-A
• chr9-95467197-T-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.2479A>G​(p.Ser827Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,614,258 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S827N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:6 O:1
• Conservation: PhyloP100: 2.55
• Publications: 23 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

LOC100507346 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 17 uncertain in NM_000264.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.013190687).
• BP6: Variant 9-95467197-T-C is Benign according to our data. Variant chr9-95467197-T-C is described in ClinVar as Benign. ClinVar VariationId is 8223.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 = 0.000459 (70/152368) while in subpopulation EAS AF = 0.0135 (70/5192). AF 95% confidence interval is 0.0109. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 70 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.2479A>G	p.Ser827Gly	missense	Exon 15 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.2476A>G	p.Ser826Gly	missense	Exon 15 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.2323A>G	p.Ser775Gly	missense	Exon 14 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.2479A>G	p.Ser827Gly	missense	Exon 15 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2476A>G	p.Ser826Gly	missense	Exon 15 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.2026A>G	p.Ser676Gly	missense	Exon 15 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0136

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000986 AC: 248 AN: 251484 AF XY: 0.00100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000237 AC: 347 AN: 1461890 Hom.: 3 Cov.: 33 AF XY: 0.000239 AC XY: 174 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00756 AC: 300 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.000459 AC: 70 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74522

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000309 Hom.: 2

Bravo AF: 0.000480

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	not provided (2)
-	-	1	Gorlin syndrome (1)
1	-	-	Holoprosencephaly 7 (1)
-	-	1	not specified (2)
-	-	1	PTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.33	N
PhyloP100		2.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.43	T
Sift4G	Benign	0.46	T
Polyphen		0.0040	B
Vest4		0.46
MVP		0.95
MPC		0.51
ClinPred		0.033	T
GERP RS		4.3
Varity_R		0.22
gMVP		0.59
Mutation Taster		=87/13	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: rs199476092; hg19: chr9-98229479;