9-95469931-C-T

Position:

• chr9-95469931-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000264.5(PTCH1):​c.1729G>A​(p.Ala577Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 0.9980
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57

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]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain SSD (size 160) in uniprot entity PTC1_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) in NM_000264.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.1729G>A	p.Ala577Thr	missense_variant, splice_region_variant	13/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.1726G>A	p.Ala576Thr	missense_variant, splice_region_variant	13/24	ENST00000437951.6	NP_001077072.1
LOC100507346	NR_038982.1	n.1869C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.1729G>A	p.Ala577Thr	missense_variant, splice_region_variant	13/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.1726G>A	p.Ala576Thr	missense_variant, splice_region_variant	13/24	5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 11, 2018

This sequence change replaces alanine with threonine at codon 577 of the PTCH1 protein (p.Ala577Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 453798). 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. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2019

The p.A577T variant (also known as c.1729G>A) is located in coding exon 13 of the PTCH1 gene. The alanine at codon 577 is replaced by threonine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 13. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;.;.;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;D;.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.018	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;D;D;.
Polyphen		0.29	B;D;D;B;B;D;P;.
Vest4		0.84
MutPred		0.64		Gain of helix (P = 0.1736);.;.;.;.;.;.;.;
MVP		0.75
MPC		0.84
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.59
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554695631; hg19: chr9-98232213;