X-23393100-C-T

Variant names:

• chrX-23393100-C-T
• rs992351585
• NM_173495.3:c.1582C>T

Variant summary

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

The NM_173495.3(PTCHD1):​c.1582C>T​(p.Leu528Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,097,216 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: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: PTCHD1 NM_173495.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:1
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCHD1	NM_173495.3	c.1582C>T	p.Leu528Phe	missense_variant	Exon 3 of 3	ENST00000379361.5	NP_775766.2
PTCHD1	XM_011545449.4	c.1582C>T	p.Leu528Phe	missense_variant	Exon 4 of 4		XP_011543751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCHD1	ENST00000379361.5	c.1582C>T	p.Leu528Phe	missense_variant	Exon 3 of 3	1	NM_173495.3	ENSP00000368666.4
PTCHD1	ENST00000456522.1	c.*417C>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000406663.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362580

Gnomad4 AFR exome AF: 0.0000758

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.: 23

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 07, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1582C>T (p.L528F) alteration is located in coding exon 3 of the PTCHD1 gene. This alteration results from a C to T substitution at nucleotide position 1582, causing the Leucine (L) at amino acid position 528 to be replaced by a phenylalanine (F). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the PTCHD1 c.1582C>T alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.L528 amino acid is conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.L528F alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.020	D
Sift4G	Benign	0.12	T
Polyphen		0.42	B
Vest4		0.31
MutPred		0.62		Gain of glycosylation at S529 (P = 0.1014);
MVP		0.86
MPC		1.4
ClinPred		0.92	D
GERP RS		5.0
Varity_R		0.64
gMVP		0.43

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;