rs992351585

Positions:

• chrX-23393100-C-A
• chrX-23393100-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173495.3(PTCHD1):​c.1582C>A​(p.Leu528Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,097,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L528F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: PTCHD1 NM_173495.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3903128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCHD1	NM_173495.3	c.1582C>A	p.Leu528Ile	missense_variant	3/3	ENST00000379361.5
PTCHD1	XM_011545449.4	c.1582C>A	p.Leu528Ile	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCHD1	ENST00000379361.5	c.1582C>A	p.Leu528Ile	missense_variant	3/3	1	NM_173495.3	P1
PTCHD1	ENST00000456522.1	c.*417C>A		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183275 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	0.84	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.29
Sift	Benign	0.49	T
Sift4G	Benign	1.0	T
Polyphen		0.42	B
Vest4		0.33
MutPred		0.48		Gain of glycosylation at S529 (P = 0.0797);
MVP		0.69
MPC		0.89
ClinPred		0.31	T
GERP RS		5.0
Varity_R		0.41
gMVP		0.19

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: rs992351585; hg19: chrX-23411217;