rs1060499778

Variant names:

• chrX-23379781-A-C
• rs1060499778
• NM_173495.3:c.542A>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 rank	MANE	Protein	UniProt
PTCHD1	NM_173495.3	c.542A>C	p.Lys181Thr	missense_variant	Exon 2 of 3	ENST00000379361.5	NP_775766.2
PTCHD1	XM_011545449.4	c.542A>C	p.Lys181Thr	missense_variant	Exon 3 of 4		XP_011543751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCHD1	ENST00000379361.5	c.542A>C	p.Lys181Thr	missense_variant	Exon 2 of 3	1	NM_173495.3	ENSP00000368666.4
PTCHD1	ENST00000456522.1	c.157-12750A>C		intron_variant	Intron 1 of 1	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

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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;