rs1555912675

Positions:

• chrX-23392681-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000379361.5(PTCHD1):​c.1163T>G​(p.Ile388Arg) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PTCHD1 ENST00000379361.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCHD1	NM_173495.3	c.1163T>G	p.Ile388Arg	missense_variant	3/3	ENST00000379361.5	NP_775766.2
PTCHD1	XM_011545449.4	c.1163T>G	p.Ile388Arg	missense_variant	4/4		XP_011543751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCHD1	ENST00000456522.1	c.310T>G	p.Ter104GluextTer37	stop_lost	2/2	1		ENSP00000406663
PTCHD1	ENST00000379361.5	c.1163T>G	p.Ile388Arg	missense_variant	3/3	1	NM_173495.3	ENSP00000368666	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Benign	0.81
DEOGEN2	Uncertain	0.77	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.85	P
Vest4		0.69
MutPred		0.87		Gain of methylation at I388 (P = 0.0014);
MVP		1.0
MPC		2.0
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.97

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: rs1555912675; hg19: chrX-23410798;