X-23334970-C-G

Position:

• chrX-23334970-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_173495.3(PTCHD1):​c.95C>G​(p.Pro32Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,460 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P32L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PTCHD1 NM_173495.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.50

Genes affected

PTCHD1 (HGNC:26392): (patched domain containing 1) This gene encodes a membrane protein with a patched domain. The encoded protein is similar to Drosophila proteins which act as receptors for the morphogen sonic hedgehog. Deletions in this gene, which is located on the X chromosome, are associated with intellectual disability and autism (PMID: 21091464, PMID: 20844286). [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant X-23334970-C-G is Pathogenic according to our data. Variant chrX-23334970-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1064443.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCHD1	NM_173495.3	c.95C>G	p.Pro32Arg	missense_variant	1/3	ENST00000379361.5
PTCHD1	XM_011545449.4	c.95C>G	p.Pro32Arg	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCHD1	ENST00000379361.5	c.95C>G	p.Pro32Arg	missense_variant	1/3	1	NM_173495.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096460 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Apr 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.85		Gain of methylation at P32 (P = 0.017);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.93
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-23353087;