Genetic Variant PDZD4:p.Arg128Cys (chrX-153807302-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001303512.2(PDZD4):c.382C>T(p.Arg128Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,209,340 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.00011 ( 0 hom. 39 hem. )

Consequence

PDZD4
NM_001303512.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

Variant links:

Genes affected

PDZD4 (HGNC:21167): (PDZ domain containing 4) Predicted to be located in cell cortex. [provided by Alliance of Genome Resources, Apr 2022]

PDZD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.360239).

BS2

High Hemizygotes in GnomAdExome4 at 39 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD4	NM_001303512.2 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 3 of 8	ENST00000393758.7	NP_001290441.1	Q76G19Q17RL8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZD4	ENST00000393758.7 link	c.382C>T	p.Arg128Cys	missense_variant	Exon 3 of 8	1	NM_001303512.2	ENSP00000377355.3		Q17RL8

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

113068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35216

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000278

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000939

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000675

AC:

AN:

177859

Hom.:

AF XY:

0.0000468

AC XY:

AN XY:

64087

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000730

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000140

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

116

AN:

1096221

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

362297

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000261

GnomAD4 genome

AF:

0.0000530

AC:

AN:

113119

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35277

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000279

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000939

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000661

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.364C>T (p.R122C) alteration is located in exon 3 (coding exon 3) of the PDZD4 gene. This alteration results from a C to T substitution at nucleotide position 364, causing the arginine (R) at amino acid position 122 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.8

D;.

REVEL

Benign

0.16

Sift

Benign

0.042

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.45

MutPred

0.47

Loss of solvent accessibility (P = 0.0561);.;

MVP

0.35

MPC

0.51

ClinPred

0.61

GERP RS

4.8

Varity_R

0.32

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over