rs1060499778

Positions:

• chrX-23379781-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_173495.3(PTCHD1):​c.542A>C​(p.Lys181Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,207 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: PTCHD1 NM_173495.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.56

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-23379781-A-C is Pathogenic according to our data. Variant chrX-23379781-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-23379781-A-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.29159912). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCHD1	NM_173495.3	c.542A>C	p.Lys181Thr	missense_variant	2/3	ENST00000379361.5	NP_775766.2
PTCHD1	XM_011545449.4	c.542A>C	p.Lys181Thr	missense_variant	3/4		XP_011543751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCHD1	ENST00000379361.5	c.542A>C	p.Lys181Thr	missense_variant	2/3	1	NM_173495.3	ENSP00000368666.4
PTCHD1	ENST00000456522.1	c.157-12750A>C		intron_variant		1		ENSP00000406663.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098207 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363561

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: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autism, susceptibility to, X-linked 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PTCHD1 related disorder (ClinVar ID: VCV000402218, PMID:26539891). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 33856728, PS3_S). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.29
Sift	Benign	0.18	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.38
MutPred		0.73		Loss of methylation at K181 (P = 0.0106);
MVP		0.72
MPC		0.71
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.27
gMVP		0.88

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: rs1060499778; hg19: chrX-23397898;