chrX-23334877-T-C

Position:

• chrX-23334877-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_173495.3(PTCHD1):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000926 in 1,080,181 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 (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: PTCHD1 NM_173495.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.18

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-23334877-T-C is Pathogenic according to our data. Variant chrX-23334877-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424379.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCHD1	NM_173495.3	c.2T>C	p.Met1?	start_lost	1/3	ENST00000379361.5	NP_775766.2
PTCHD1	XM_011545449.4	c.2T>C	p.Met1?	start_lost, splice_region_variant	2/4		XP_011543751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCHD1	ENST00000379361.5	c.2T>C	p.Met1?	start_lost	1/3	1	NM_173495.3	ENSP00000368666	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.26e-7 AC: 1 AN: 1080181 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 351147

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: 0.00

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

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 24, 2023

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; The protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35328080) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.92		Gain of catalytic residue at M1 (P = 0.0177);
MVP		0.97
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.92
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs1064796945; hg19: chrX-23352994;