NM_173791.5:c.*5770T>G

Variant names:

• chr10-117277498-A-C
• rs10377
• NM_173791.5:c.*5770T>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_173791.5(PDZD8):​c.*5770T>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 0.496 in 269,082 control chromosomes in the GnomAD database, including 34,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16501 hom., cov: 33)
  • Exomes 𝑓: 0.55 (17515 hom.)
• Consequence: PDZD8 NM_173791.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.82
• Publications: 8 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]

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)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 10-117277498-A-C is Benign according to our data. Variant chr10-117277498-A-C is described in ClinVar as [Benign]. Clinvar id is 1175418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD8	NM_173791.5	c.*5770T>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000334464.7	NP_776152.1
SLC18A2	NM_003054.6	c.*232A>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000644641.2	NP_003045.2
PDZD8	XM_005269518.5	c.*5770T>G		3_prime_UTR_variant	Exon 4 of 4		XP_005269575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZD8	ENST00000334464.7	c.*5770T>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_173791.5	ENSP00000334642.5
SLC18A2	ENST00000644641.2	c.*232A>C		3_prime_UTR_variant	Exon 16 of 16		NM_003054.6	ENSP00000496339.1
SLC18A2	ENST00000497497.1	n.2193A>C		non_coding_transcript_exon_variant	Exon 15 of 15	2

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69285 AN: 152014 Hom.: 16504 Cov.: 33

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.454

GnomAD4 exome AF: 0.548 AC: 64055 AN: 116952 Hom.: 17515 Cov.: 2 AF XY: 0.548 AC XY: 32764 AN XY: 59778

African (AFR) AF: 0.349 AC: 1309 AN: 3746

American (AMR) AF: 0.619 AC: 2457 AN: 3972

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 2340 AN: 4766

East Asian (EAS) AF: 0.589 AC: 5944 AN: 10096

South Asian (SAS) AF: 0.567 AC: 1371 AN: 2418

European-Finnish (FIN) AF: 0.549 AC: 3665 AN: 6670

Middle Eastern (MID) AF: 0.442 AC: 251 AN: 568

European-Non Finnish (NFE) AF: 0.552 AC: 42281 AN: 76628

Other (OTH) AF: 0.549 AC: 4437 AN: 8088

GnomAD4 genome AF: 0.455 AC: 69294 AN: 152130 Hom.: 16501 Cov.: 33 AF XY: 0.455 AC XY: 33833 AN XY: 74376

African (AFR) AF: 0.310 AC: 12872 AN: 41496

American (AMR) AF: 0.508 AC: 7760 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1598 AN: 3470

East Asian (EAS) AF: 0.538 AC: 2787 AN: 5180

South Asian (SAS) AF: 0.498 AC: 2403 AN: 4828

European-Finnish (FIN) AF: 0.474 AC: 5011 AN: 10566

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.517 AC: 35159 AN: 67992

Other (OTH) AF: 0.449 AC: 948 AN: 2110

Alfa AF: 0.459 Hom.: 2452

Bravo AF: 0.457

Asia WGS AF: 0.487 AC: 1682 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.84
PhyloP100		2.8
Mutation Taster		=100/0	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: rs10377; hg19: chr10-119037009; COSMIC: COSV53690199;