rs144982584

chrX-23379896-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_173495.3(PTCHD1):c.657C>T(p.Asn219=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,210,242 control chromosomes in the GnomAD database, including 3 homozygotes. There are 1,014 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., 47 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (2 hom. 967 hem.)
• Consequence: PTCHD1 NM_173495.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.01

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant X-23379896-C-T is Benign according to our data. Variant chrX-23379896-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 195428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.01 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 47 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCHD1	NM_173495.3	c.657C>T	p.Asn219=	synonymous_variant	2/3	ENST00000379361.5
PTCHD1	XM_011545449.4	c.657C>T	p.Asn219=	synonymous_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCHD1	ENST00000379361.5	c.657C>T	p.Asn219=	synonymous_variant	2/3	1	NM_173495.3	P1
PTCHD1	ENST00000456522.1	c.159-12635C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 198 AN: 112196 Hom.: 1 Cov.: 23 AF XY: 0.00137 AC XY: 47 AN XY: 34346

Gnomad AFR AF: 0.000551

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000753

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000376

Gnomad FIN AF: 0.00229

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.00189 AC: 347 AN: 183471 Hom.: 1 AF XY: 0.00199 AC XY: 135 AN XY: 67901

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.000510

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00369

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00270 AC: 2966 AN: 1097991 Hom.: 2 Cov.: 31 AF XY: 0.00266 AC XY: 967 AN XY: 363347

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.000625

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000573

Gnomad4 FIN exome AF: 0.00375

Gnomad4 NFE exome AF: 0.00312

Gnomad4 OTH exome AF: 0.00271

GnomAD4 genome AF: 0.00177 AC: 199 AN: 112251 Hom.: 1 Cov.: 23 AF XY: 0.00137 AC XY: 47 AN XY: 34411

Gnomad4 AFR AF: 0.000549

Gnomad4 AMR AF: 0.000752

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000753

Gnomad4 FIN AF: 0.00229

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00135 Hom.: 9

Bravo AF: 0.00155

EpiCase AF: 0.00300

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2017

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
BayesDel_noAF	Benign	-0.44
Cadd	Benign	10
Dann	Benign	0.61

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

LitVar

Other links and lift over

dbSNP: rs144982584; hg19: chrX-23398013;