chrX-23334895-A-T

Position:

• chrX-23334895-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173495.3(PTCHD1):​c.20A>T​(p.His7Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000092 in 1,086,860 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: PTCHD1 NM_173495.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.35

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCHD1	NM_173495.3	c.20A>T	p.His7Leu	missense_variant	1/3	ENST00000379361.5	NP_775766.2
PTCHD1	XM_011545449.4	c.20A>T	p.His7Leu	missense_variant	2/4		XP_011543751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCHD1	ENST00000379361.5	c.20A>T	p.His7Leu	missense_variant	1/3	1	NM_173495.3	ENSP00000368666	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1086860 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 355292

Gnomad4 AFR exome AF: 0.0000382

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

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 29, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.014	D
Polyphen		0.018	B
Vest4		0.52
MutPred		0.39		Loss of disorder (P = 0.0496);
MVP		1.0
MPC		1.7
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.63
gMVP		0.86

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: rs1921120061; hg19: chrX-23353012;