rs1555912049

Variant names:

• chrX-23379828-GTGCACAGCAAAGAC-G
• rs1555912049
• NM_173495.3:c.590_603delTGCACAGCAAAGAC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_173495.3(PTCHD1):​c.590_603delTGCACAGCAAAGAC​(p.Val197AlafsTer22) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PTCHD1 NM_173495.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.98
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-23379828-GTGCACAGCAAAGAC-G is Pathogenic according to our data. Variant chrX-23379828-GTGCACAGCAAAGAC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 521561.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCHD1	NM_173495.3	c.590_603delTGCACAGCAAAGAC	p.Val197AlafsTer22	frameshift_variant	Exon 2 of 3	ENST00000379361.5	NP_775766.2
PTCHD1	XM_011545449.4	c.590_603delTGCACAGCAAAGAC	p.Val197AlafsTer22	frameshift_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.590_603delTGCACAGCAAAGAC	p.Val197AlafsTer22	frameshift_variant	Exon 2 of 3	1	NM_173495.3	ENSP00000368666.4
PTCHD1	ENST00000456522.1	c.157-12702_157-12689delTGCACAGCAAAGAC		intron_variant	Intron 1 of 1	1		ENSP00000406663.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Mar 20, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555912049; hg19: chrX-23397945;