Genetic Variant NM_173791.5:c.*3620T>G (chr10-117279648-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_173791.5(PDZD8):c.*3620T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,108 control chromosomes in the GnomAD database, including 4,046 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4046 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

PDZD8
NM_173791.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.370

Publications

6 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 links:

SLC18A2 (HGNC:10935): (solute carrier family 18 member A2) This gene encodes an transmembrane protein that functions as an ATP-dependent transporter of monoamines, such as dopamine, norepinephrine, serotonin, and histamine. This protein transports amine neurotransmitters into synaptic vesicles. Polymorphisms in this gene may be associated with schizophrenia, bipolar disorder, and other neurological/psychiatric ailments. [provided by RefSeq, Jun 2018]

SLC18A2 Gene-Disease associations (from GenCC):

brain dopamine-serotonin vesicular transport disease
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
parkinsonism-dystonia, infantile, 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SLC18A2 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.272 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD8	NM_173791.5	MANE Select	c.*3620T>G		3_prime_UTR	Exon 5 of 5	NP_776152.1
	SLC18A2	NM_003054.6	MANE Select	c.*2382A>C		downstream_gene	N/A	NP_003045.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PDZD8	ENST00000334464.7	TSL:1 MANE Select	c.*3620T>G	3_prime_UTR	Exon 5 of 5	ENSP00000334642.5
SLC18A2	ENST00000644641.2	MANE Select	c.*2382A>C	downstream_gene	N/A	ENSP00000496339.1
SLC18A2	ENST00000497497.1	TSL:2	n.*218A>C	downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.218

AC:

33086

AN:

151990

Hom.:

4045

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.194

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.245

Gnomad EAS

AF:

0.0164

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.332

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.227

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.217

AC:

33083

AN:

152108

Hom.:

4046

Cov.:

AF XY:

0.217

AC XY:

16109

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.133

AC:

5527

AN:

41518

American (AMR)

AF:

0.188

AC:

2875

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

850

AN:

3468

East Asian (EAS)

AF:

0.0164

AC:

AN:

5170

South Asian (SAS)

AF:

0.161

AC:

775

AN:

4824

European-Finnish (FIN)

AF:

0.332

AC:

3501

AN:

10556

Middle Eastern (MID)

AF:

0.340

AC:

100

AN:

294

European-Non Finnish (NFE)

AF:

0.275

AC:

18719

AN:

67976

Other (OTH)

AF:

0.225

AC:

474

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1286

2572

3857

5143

6429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

348

696

1044

1392

1740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.254

Hom.:

710

Bravo

AF:

0.201

Asia WGS

AF:

0.0900

AC:

313

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.30

(source)

DANN

Benign

0.60

PhyloP100

-0.37

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