NM_173791.5:c.2690G>A

Variant names:

• chr10-117284043-C-T
• rs363294
• NM_173791.5:c.2690G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173791.5(PDZD8):​c.2690G>A​(p.Arg897Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0505 in 1,614,066 control chromosomes in the GnomAD database, including 2,526 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R897G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (164 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2362 hom.)
• Consequence: PDZD8 NM_173791.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.870
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013818741).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173791.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD8	NM_173791.5	MANE Select	c.2690G>A	p.Arg897Gln	missense	Exon 5 of 5	NP_776152.1	Q8NEN9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD8	ENST00000334464.7	TSL:1 MANE Select	c.2690G>A	p.Arg897Gln	missense	Exon 5 of 5	ENSP00000334642.5	Q8NEN9
	PDZD8	ENST00000868795.1		c.2567G>A	p.Arg856Gln	missense	Exon 4 of 4	ENSP00000538854.1

Frequencies

GnomAD3 genomes AF: 0.0391 AC: 5945 AN: 152124 Hom.: 161 Cov.: 32

Gnomad AFR AF: 0.00934

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.00963

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0564

Gnomad OTH AF: 0.0439

GnomAD2 exomes AF: 0.0491 AC: 12320 AN: 251140 AF XY: 0.0526

Gnomad AFR exome AF: 0.00812

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.00850

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0573

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0517 AC: 75593 AN: 1461824 Hom.: 2362 Cov.: 34 AF XY: 0.0535 AC XY: 38939 AN XY: 727212

African (AFR) AF: 0.00944 AC: 316 AN: 33480

American (AMR) AF: 0.0236 AC: 1057 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2836 AN: 26136

East Asian (EAS) AF: 0.0116 AC: 461 AN: 39694

South Asian (SAS) AF: 0.0830 AC: 7160 AN: 86252

European-Finnish (FIN) AF: 0.0342 AC: 1829 AN: 53418

Middle Eastern (MID) AF: 0.0692 AC: 399 AN: 5768

European-Non Finnish (NFE) AF: 0.0526 AC: 58473 AN: 1111960

Other (OTH) AF: 0.0507 AC: 3062 AN: 60392

GnomAD4 genome AF: 0.0392 AC: 5962 AN: 152242 Hom.: 164 Cov.: 32 AF XY: 0.0383 AC XY: 2849 AN XY: 74440

African (AFR) AF: 0.00936 AC: 389 AN: 41538

American (AMR) AF: 0.0265 AC: 405 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3470

East Asian (EAS) AF: 0.00965 AC: 50 AN: 5180

South Asian (SAS) AF: 0.0818 AC: 395 AN: 4826

European-Finnish (FIN) AF: 0.0349 AC: 370 AN: 10606

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0564 AC: 3839 AN: 68010

Other (OTH) AF: 0.0501 AC: 106 AN: 2116

Alfa AF: 0.0549 Hom.: 1284

Bravo AF: 0.0360

TwinsUK AF: 0.0583 AC: 216

ALSPAC AF: 0.0519 AC: 200

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0574 AC: 494

ExAC AF: 0.0496 AC: 6025

Asia WGS AF: 0.0480 AC: 168 AN: 3478

EpiCase AF: 0.0631

EpiControl AF: 0.0610

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.87
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.10
Sift	Benign	0.048	D
Sift4G	Benign	0.089	T
Polyphen		0.0090	B
Vest4		0.021
MPC		0.25
ClinPred		0.0065	T
GERP RS		1.7
Varity_R		0.061
gMVP		0.55
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs363294; hg19: chr10-119043554; COSMIC: COSV53692301; COSMIC: COSV53692301;