rs992351585

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-23393100-C-T
• chrX-23393100-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 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:2
• Conservation: PhyloP100: 5.80
• Publications: 1 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

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.1582C>T	p.Leu528Phe	missense	Exon 3 of 3	NP_775766.2	Q96NR3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCHD1	ENST00000379361.5	TSL:1 MANE Select	c.1582C>T	p.Leu528Phe	missense	Exon 3 of 3	ENSP00000368666.4	Q96NR3-1
	PTCHD1	ENST00000456522.1	TSL:1	c.*417C>T		3_prime_UTR	Exon 2 of 2	ENSP00000406663.1	H7C2M0
	PTCHD1	ENST00000903588.1		c.1582C>T	p.Leu528Phe	missense	Exon 4 of 4	ENSP00000573647.1

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

African (AFR) AF: 0.0000758 AC: 2 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54123

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40475

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841247

Other (OTH) AF: 0.00 AC: 0 AN: 46053

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.8
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
Mutation Taster		=61/39	polymorphism

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: rs992351585; hg19: chrX-23411217;