rs1060499778

Variant names:

• chrX-23379781-A-C
• rs1060499778
• NM_173495.3:c.542A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K181N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: PTCHD1 NM_173495.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.56
• Publications: 5 publications found

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]

PTCHD1 Gene-Disease associations (from GenCC):

• autism, susceptibility to, X-linked 4

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402218.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29159912). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173495.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCHD1	NM_173495.3	MANE Select	c.542A>C	p.Lys181Thr	missense	Exon 2 of 3	NP_775766.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCHD1	ENST00000379361.5	TSL:1 MANE Select	c.542A>C	p.Lys181Thr	missense	Exon 2 of 3	ENSP00000368666.4
	PTCHD1	ENST00000456522.1	TSL:1	c.157-12750A>C		intron	N/A	ENSP00000406663.1
	PTCHD1	ENST00000903588.1		c.542A>C	p.Lys181Thr	missense	Exon 3 of 4	ENSP00000573647.1

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

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842095

Other (OTH) AF: 0.0000217 AC: 1 AN: 46096

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal brain morphology (1)
1	-	-	Autism, susceptibility to, X-linked 4 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.6
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
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1060499778; hg19: chrX-23397898;