Genetic Variant NM_173791.5:c.2786A>C (chr10-117283947-T-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_173791.5(PDZD8):c.2786A>C(p.Asn929Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00732 in 1,614,230 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. N929S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 54 hom. )

Consequence

PDZD8
NM_173791.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.46

Publications

7 publications found

Variant links:

Genes affected

PDZD8 (HGNC:26974): (PDZ domain containing 8) Predicted to enable lipid binding activity and metal ion binding activity. Involved in several processes, including mitochondrial calcium ion homeostasis; mitochondrion-endoplasmic reticulum membrane tethering; and regulation of cell morphogenesis. Located in endoplasmic reticulum membrane and mitochondria-associated endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

PDZD8 Gene-Disease associations (from GenCC):

intellectual developmental disorder with autism and dysmorphic facies
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

PDZD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036906898).

BS2

High Homozygotes in GnomAdExome4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD8	NM_173791.5 link	c.2786A>C	p.Asn929Thr	missense_variant	Exon 5 of 5	ENST00000334464.7	NP_776152.1	Q8NEN9
PDZD8	XM_005269518.5 link	c.2663A>C	p.Asn888Thr	missense_variant	Exon 4 of 4		XP_005269575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZD8	ENST00000334464.7 link	c.2786A>C	p.Asn929Thr	missense_variant	Exon 5 of 5	1	NM_173791.5	ENSP00000334642.5		Q8NEN9

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

789

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00696

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00789

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00530

AC:

1333

AN:

251346

AF XY:

0.00523

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00333

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00781

Gnomad NFE exome

AF:

0.00818

Gnomad OTH exome

AF:

0.00833

GnomAD4 exome

AF:

0.00755

AC:

11031

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00735

AC XY:

5344

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33480

American (AMR)

AF:

0.00387

AC:

173

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00429

AC:

112

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00854

AC:

456

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00885

AC:

9837

AN:

1111998

Other (OTH)

AF:

0.00647

AC:

391

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

776

1552

2328

3104

3880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00518

AC:

789

AN:

152352

Hom.:

Cov.:

AF XY:

0.00487

AC XY:

363

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41586

American (AMR)

AF:

0.00470

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00696

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00789

AC:

537

AN:

68026

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00632

Hom.:

Bravo

AF:

0.00502

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.00518

AC:

629

EpiCase

AF:

0.00671

EpiControl

AF:

0.00693

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0073

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.72

M_CAP

Benign

0.037

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.34

PhyloP100

2.5

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.80

REVEL

Benign

0.18

Sift

Benign

0.28

Sift4G

Benign

0.16

Polyphen

0.13

Vest4

0.080

MVP

0.47

MPC

0.22

ClinPred

0.0078

GERP RS

3.2

Varity_R

0.045

gMVP

0.45

Mutation Taster

=70/30

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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NM_173791.5:c.2786A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over