NM_173495.3:c.517A>G

Variant names:

• chrX-23379756-A-G
• rs147324438
• NM_173495.3:c.517A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 5.30
• Publications: 6 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 -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

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.517A>G	p.Ile173Val	missense	Exon 2 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.517A>G	p.Ile173Val	missense	Exon 2 of 3	ENSP00000368666.4	Q96NR3-1
	PTCHD1	ENST00000456522.1	TSL:1	c.157-12775A>G		intron	N/A	ENSP00000406663.1	H7C2M0
	PTCHD1	ENST00000903588.1		c.517A>G	p.Ile173Val	missense	Exon 3 of 4	ENSP00000573647.1

Frequencies

GnomAD3 genomes AF: 0.000324 AC: 36 AN: 111016 Hom.: 0 Cov.: 23

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: 73 AN: 183516 AF XY: 0.000471

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.: 2 Cov.: 31 AF XY: 0.000366 AC XY: 133 AN XY: 363582

African (AFR) AF: 0.0000379 AC: 1 AN: 26401

American (AMR) AF: 0.000312 AC: 11 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19386

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

South Asian (SAS) AF: 0.000757 AC: 41 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4137

European-Non Finnish (NFE) AF: 0.000313 AC: 264 AN: 842116

Other (OTH) AF: 0.000412 AC: 19 AN: 46095

GnomAD4 genome AF: 0.000324 AC: 36 AN: 111069 Hom.: 0 Cov.: 23 AF XY: 0.000421 AC XY: 14 AN XY: 33263

African (AFR) AF: 0.00 AC: 0 AN: 30493

American (AMR) AF: 0.000478 AC: 5 AN: 10452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3531

South Asian (SAS) AF: 0.000385 AC: 1 AN: 2599

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5953

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000566 AC: 30 AN: 52982

Other (OTH) AF: 0.00 AC: 0 AN: 1517

Alfa AF: 0.000418 Hom.: 19

Bravo AF: 0.000298

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.000654

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autism, susceptibility to, X-linked 4 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	PTCHD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.14	N
PhyloP100		5.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.44
Sift	Benign	0.70	T
Sift4G	Benign	1.0	T
Polyphen		0.11	B
Vest4		0.099
MVP		0.88
MPC		0.55
ClinPred		0.044	T
GERP RS		5.1
Varity_R		0.17
gMVP		0.77
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: rs147324438; hg19: chrX-23397873;