Genetic Variant NM_001303512.2:c.1349C>A (chrX-153804332-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001303512.2(PDZD4):c.1349C>A(p.Ala450Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,092,350 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A450T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.000015 ( 0 hom. 5 hem. )

Consequence

PDZD4
NM_001303512.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0340

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07368505).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303512.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDZD4	NM_001303512.2	MANE Select	c.1349C>A	p.Ala450Glu	missense	Exon 8 of 8	NP_001290441.1	Q17RL8
PDZD4	NM_032512.5		c.1331C>A	p.Ala444Glu	missense	Exon 8 of 8	NP_115901.2
PDZD4	NM_001303515.2		c.1106C>A	p.Ala369Glu	missense	Exon 8 of 8	NP_001290444.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDZD4	ENST00000393758.7	TSL:1 MANE Select	c.1349C>A	p.Ala450Glu	missense	Exon 8 of 8	ENSP00000377355.3	Q17RL8
PDZD4	ENST00000164640.8	TSL:1	c.1331C>A	p.Ala444Glu	missense	Exon 8 of 8	ENSP00000164640.4	Q76G19-1
PDZD4	ENST00000544474.5	TSL:1	c.1004C>A	p.Ala335Glu	missense	Exon 6 of 6	ENSP00000442033.1	Q76G19-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000562

AC:

AN:

177871

AF XY:

0.0000154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

1092350

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

359818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26354

American (AMR)

AF:

0.00

AC:

AN:

35127

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19349

East Asian (EAS)

AF:

0.00

AC:

AN:

30128

South Asian (SAS)

AF:

0.00

AC:

AN:

54039

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36989

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3933

European-Non Finnish (NFE)

AF:

0.0000178

AC:

AN:

840502

Other (OTH)

AF:

0.0000218

AC:

AN:

45929

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.87

CADD

Benign

7.8

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.076

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.82

M_CAP

Benign

0.028

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.20

PhyloP100

-0.034

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.21

REVEL

Benign

0.044

Sift

Benign

0.061

Sift4G

Benign

0.92

Polyphen

0.035

Vest4

0.066

MutPred

0.14

Gain of solvent accessibility (P = 0.0261)

MVP

0.12

MPC

1.0

ClinPred

0.027

GERP RS

0.94

Varity_R

0.069

gMVP

0.69

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over