NM_173495.3:c.1332C>T

Variant names:

• chrX-23392850-C-T
• rs138702144
• NM_173495.3:c.1332C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_173495.3(PTCHD1):​c.1332C>T​(p.Val444Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,210,524 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 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 0.00061 (0 hom., 20 hem., cov: 23)
  • Exomes 𝑓: 0.000077 (0 hom. 25 hem.)
• Consequence: PTCHD1 NM_173495.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.929
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-23392850-C-T is Benign according to our data. Variant chrX-23392850-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211966.
• BP7: Synonymous conserved (PhyloP=0.929 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 20 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCHD1	NM_173495.3	MANE Select	c.1332C>T	p.Val444Val	synonymous	Exon 3 of 3	NP_775766.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCHD1	ENST00000379361.5	TSL:1 MANE Select	c.1332C>T	p.Val444Val	synonymous	Exon 3 of 3	ENSP00000368666.4
	PTCHD1	ENST00000456522.1	TSL:1	c.*167C>T		3_prime_UTR	Exon 2 of 2	ENSP00000406663.1

Frequencies

GnomAD3 genomes AF: 0.000613 AC: 69 AN: 112569 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 31 AN: 182977 AF XY: 0.0000888

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000765 AC: 84 AN: 1097904 Hom.: 0 Cov.: 33 AF XY: 0.0000688 AC XY: 25 AN XY: 363258

African (AFR) AF: 0.00223 AC: 59 AN: 26402

American (AMR) AF: 0.000284 AC: 10 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40460

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

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841883

Other (OTH) AF: 0.000217 AC: 10 AN: 46086

GnomAD4 genome AF: 0.000613 AC: 69 AN: 112620 Hom.: 0 Cov.: 23 AF XY: 0.000575 AC XY: 20 AN XY: 34790

African (AFR) AF: 0.00213 AC: 66 AN: 31043

American (AMR) AF: 0.0000938 AC: 1 AN: 10663

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.000371 AC: 1 AN: 2697

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6197

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000187 AC: 1 AN: 53337

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.000427 Hom.: 1

Bravo AF: 0.000695

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.8
DANN	Benign	0.69
PhyloP100		0.93
Mutation Taster		=99/1	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: rs138702144; hg19: chrX-23410967;