rs755092661

Variant names:

• chr9-95447426-T-C
• rs755092661
• NM_000264.5:c.3830A>G

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.3830A>G​(p.His1277Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. H1277Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.07
• 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, Labcorp Genetics (formerly Invitae), Orphanet
• 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=0.10401043).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.3830A>G	p.His1277Arg	missense	Exon 23 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3827A>G	p.His1276Arg	missense	Exon 23 of 24	NP_001077072.1
	PTCH1	NM_001354918.2		c.3674A>G	p.His1225Arg	missense	Exon 22 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.3830A>G	p.His1277Arg	missense	Exon 23 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3827A>G	p.His1276Arg	missense	Exon 23 of 24	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.3377A>G	p.His1126Arg	missense	Exon 23 of 24	ENSP00000414823.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235820 AF XY: 0.00

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: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447042 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 718932

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000304 AC: 1 AN: 32892

American (AMR) AF: 0.00 AC: 0 AN: 43152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25304

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 85114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105850

Other (OTH) AF: 0.00 AC: 0 AN: 59722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00400497), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Dec 11, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PTCH1-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces histidine with arginine at codon 1277 of the PTCH1 protein (p.His1277Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine.

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H1277R variant (also known as c.3830A>G), located in coding exon 23 of the PTCH1 gene, results from an A to G substitution at nucleotide position 3830. The histidine at codon 1277 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.0093	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.18
Sift	Benign	0.32	T
Sift4G	Benign	0.32	T
Polyphen		0.0080	B
Vest4		0.29
MutPred		0.16		Loss of glycosylation at S1274 (P = 0.1041)
MVP		0.69
MPC		0.096
ClinPred		0.049	T
GERP RS		3.7
Varity_R		0.10
gMVP		0.23
Mutation Taster		=74/26	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: rs755092661; hg19: chr9-98209708;