Genetic Variant PDZD4:p.Pro115Leu (chrX-153807340-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.344C>T(p.Pro115Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 1,208,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 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 0.000027 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000029 ( 0 hom. 11 hem. )

Consequence

PDZD4
NM_001303512.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

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=0.2927454).

BS2

High Hemizygotes in GnomAdExome4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD4	NM_001303512.2 link	c.344C>T	p.Pro115Leu	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.344C>T	p.Pro115Leu	missense_variant	Exon 3 of 8	1	NM_001303512.2	ENSP00000377355.3		Q17RL8

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

112920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35064

show subpopulations

Gnomad AFR

AF:

0.0000643

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1095295

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

361297

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000266

AC:

AN:

112920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35064

show subpopulations

Gnomad4 AFR

AF:

0.0000643

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000660

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.326C>T (p.P109L) 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 326, causing the proline (P) at amino acid position 109 to be replaced by a leucine (L). 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

0.24

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;T

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.2

D;.

REVEL

Benign

0.12

Sift

Benign

0.11

T;.

Sift4G

Benign

0.52

T;T

Polyphen

0.91

P;P

Vest4

0.40

MutPred

0.48

Loss of disorder (P = 0.0227);.;

MVP

0.22

MPC

0.35

ClinPred

0.62

GERP RS

5.6

Varity_R

0.29

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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