rs147324438

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_173495.3(PTCHD1):c.517A>G(p.Ile173Val) variant causes a missense change. The variant allele was found at a frequency of 0.000311 in 1,209,297 control chromosomes in the GnomAD database, including 2 homozygotes. There are 147 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., 14 hem., cov: 23)

Exomes 𝑓: 0.00031 ( 2 hom. 133 hem. )

Consequence

PTCHD1
NM_173495.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 5.30

Publications

6 publications found

Variant links:

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

PTCHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03401667).

BP6

Variant X-23379756-A-G is Benign according to our data. Variant chrX-23379756-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211971.

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCHD1	NM_173495.3 link	c.517A>G	p.Ile173Val	missense_variant	Exon 2 of 3	ENST00000379361.5	NP_775766.2	Q96NR3-1X5DNX9
PTCHD1	XM_011545449.4 link	c.517A>G	p.Ile173Val	missense_variant	Exon 3 of 4		XP_011543751.1	Q96NR3-1X5DNX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCHD1	ENST00000379361.5 link	c.517A>G	p.Ile173Val	missense_variant	Exon 2 of 3	1	NM_173495.3	ENSP00000368666.4		Q96NR3-1
PTCHD1	ENST00000456522.1 link	c.157-12775A>G		intron_variant	Intron 1 of 1	1		ENSP00000406663.1		H7C2M0

Frequencies

GnomAD3 genomes

AF:

0.000324

AC:

AN:

111016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000479

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000384

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000566

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000398

AC:

AN:

183516

AF XY:

0.000471

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000255

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000586

Gnomad OTH exome

AF:

0.000441

GnomAD4 exome

AF:

0.000310

AC:

340

AN:

1098228

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

133

AN XY:

363582

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26401

American (AMR)

AF:

0.000312

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.000757

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.000725

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000313

AC:

264

AN:

842116

Other (OTH)

AF:

0.000412

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000324

AC:

AN:

111069

Hom.:

Cov.:

AF XY:

0.000421

AC XY:

AN XY:

33263

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30493

American (AMR)

AF:

0.000478

AC:

AN:

10452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3531

South Asian (SAS)

AF:

0.000385

AC:

AN:

2599

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5953

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000566

AC:

AN:

52982

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000418

Hom.:

Bravo

AF:

0.000298

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 19, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20844286, 23871722) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTCHD1: BS1, BS2 -

not specified

Uncertain:1

Dec 29, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autism, susceptibility to, X-linked 4

Uncertain:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PTCHD1-related disorder

Uncertain:1

Dec 06, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PTCHD1 c.517A>G variant is predicted to result in the amino acid substitution p.Ile173Val. This variant has been reported in at least one male patient with autism spectrum disorder/ intellectual disability and found in his unaffected mother and one of his unaffected sisters. Of note, this male patient was also heterozygous for a de novo ~1 Mb deletion encompassing the entire DPYD gene (Carter. 2010. PubMed ID: 21114665; Noor et al. 2010. PubMed ID: 20844286). In vitro experimental studies have shown that PTCHD1 protein carrying the p.Ile173Val variant is expressed at levels comparable to wild type and localizes properly to the cell membrane; however, additional experiments to assess possible impacts on protein function were not performed (Halewa et al. 2021. PubMed ID: 33856728). This variant is reported in 0.084% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Benign:1

Apr 27, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

M_CAP

Benign

0.063

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.14

PhyloP100

5.3

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.50

REVEL

Uncertain

0.44

Sift

Benign

0.70

Sift4G

Benign

1.0

Polyphen

0.11

Vest4

0.099

MVP

0.88

MPC

0.55

ClinPred

0.044

GERP RS

5.1

Varity_R

0.17

gMVP

0.77

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over