dbSNP rs992351585: PTCHD1:p.Leu528Ile (chrX-23393100-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_173495.3(PTCHD1):c.1582C>A(p.Leu528Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,097,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L528F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

PTCHD1
NM_173495.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.80

Publications

1 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3903128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCHD1	NM_173495.3 link	c.1582C>A	p.Leu528Ile	missense_variant	Exon 3 of 3	ENST00000379361.5	NP_775766.2
PTCHD1	XM_011545449.4 link	c.1582C>A	p.Leu528Ile	missense_variant	Exon 4 of 4		XP_011543751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCHD1	ENST00000379361.5 link	c.1582C>A	p.Leu528Ile	missense_variant	Exon 3 of 3	1	NM_173495.3	ENSP00000368666.4
PTCHD1	ENST00000456522.1 link	c.*417C>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000406663.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183275

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362580

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54123

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40475

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841247

Other (OTH)

AF:

0.0000434

AC:

AN:

46053

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.77

PhyloP100

5.8

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.81

REVEL

Uncertain

0.29

Sift

Benign

0.49

Sift4G

Benign

1.0

Polyphen

0.42

Vest4

0.33

MutPred

0.48

Gain of glycosylation at S529 (P = 0.0797);

MVP

0.69

MPC

0.89

ClinPred

0.31

GERP RS

5.0

Varity_R

0.41

gMVP

0.19

Mutation Taster

=80/20

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over