10-117284043-C-T

Position:

• chr10-117284043-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZD8	NM_173791.5	c.2690G>A	p.Arg897Gln	missense_variant	5/5	ENST00000334464.7	NP_776152.1
PDZD8	XM_005269518.5	c.2567G>A	p.Arg856Gln	missense_variant	4/4		XP_005269575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZD8	ENST00000334464.7	c.2690G>A	p.Arg897Gln	missense_variant	5/5	1	NM_173791.5	ENSP00000334642	P1

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

GnomAD3 exomes AF: 0.0491 AC: 12320 AN: 251140 Hom.: 437 AF XY: 0.0526 AC XY: 7142 AN XY: 135732

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 SAS exome AF: 0.0843

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

Gnomad4 AFR exome AF: 0.00944

Gnomad4 AMR exome AF: 0.0236

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0116

Gnomad4 SAS exome AF: 0.0830

Gnomad4 FIN exome AF: 0.0342

Gnomad4 NFE exome AF: 0.0526

Gnomad4 OTH exome AF: 0.0507

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

Gnomad4 AFR AF: 0.00936

Gnomad4 AMR AF: 0.0265

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.00965

Gnomad4 SAS AF: 0.0818

Gnomad4 FIN AF: 0.0349

Gnomad4 NFE AF: 0.0564

Gnomad4 OTH AF: 0.0501

Alfa AF: 0.0571 Hom.: 794

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 v4.3

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
MutationTaster	Benign	1.0	N
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

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

Other links and lift over

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