Genetic Variant PDZD4:p.Asp158Asn (chrX-153806774-C-T) – 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.472G>A(p.Asp158Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000268 in 1,209,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 95 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 0.00017 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.00028 ( 0 hom. 92 hem. )

Consequence

PDZD4
NM_001303512.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13

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=0.2725816).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD4	NM_001303512.2 link	c.472G>A	p.Asp158Asn	missense_variant	Exon 4 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.472G>A	p.Asp158Asn	missense_variant	Exon 4 of 8	1	NM_001303512.2	ENSP00000377355.3		Q17RL8

Frequencies

GnomAD3 genomes

AF:

0.000170

AC:

AN:

111493

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

33675

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000946

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000264

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

182995

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

67829

show subpopulations

Gnomad AFR exome

AF:

0.0000762

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000221

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000278

AC:

305

AN:

1097903

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

AN XY:

363353

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000993

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000340

Gnomad4 OTH exome

AF:

0.000325

GnomAD4 genome

AF:

0.000170

AC:

AN:

111544

Hom.:

Cov.:

AF XY:

0.0000889

AC XY:

AN XY:

33736

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.0000945

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000264

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000359

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.454G>A (p.D152N) alteration is located in exon 4 (coding exon 4) of the PDZD4 gene. This alteration results from a G to A substitution at nucleotide position 454, causing the aspartic acid (D) at amino acid position 152 to be replaced by an asparagine (N). 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

0.18

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.78

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.82

L;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.9

D;D;N

REVEL

Benign

0.22

Sift

Uncertain

0.015

D;D;T

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.97

D;.;B

Vest4

0.23

MVP

0.60

MPC

1.8

ClinPred

0.35

GERP RS

5.3

Varity_R

0.44

gMVP

0.83

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