chr10-117277560-T-C

Variant names:

• chr10-117277560-T-C
• rs14240
• NM_173791.5:c.*5708A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_173791.5(PDZD8):​c.*5708A>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 0.469 in 174,540 control chromosomes in the GnomAD database, including 20,079 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 0.46 (16476 hom., cov: 33)
  • Exomes 𝑓: 0.56 (3603 hom.)
• Consequence: PDZD8 NM_173791.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.790
• Publications: 13 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• 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.*5708A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000334464.7	NP_776152.1
SLC18A2	NM_003054.6	c.*294T>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000644641.2	NP_003045.2
PDZD8	XM_005269518.5	c.*5708A>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.*5708A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_173791.5	ENSP00000334642.5
SLC18A2	ENST00000644641.2	c.*294T>C		3_prime_UTR_variant	Exon 16 of 16		NM_003054.6	ENSP00000496339.1
SLC18A2	ENST00000497497.1	n.2255T>C		non_coding_transcript_exon_variant	Exon 15 of 15	2

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69216 AN: 151936 Hom.: 16479 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.454

GnomAD4 exome AF: 0.563 AC: 12651 AN: 22486 Hom.: 3603 Cov.: 0 AF XY: 0.559 AC XY: 6505 AN XY: 11646

African (AFR) AF: 0.371 AC: 329 AN: 886

American (AMR) AF: 0.591 AC: 428 AN: 724

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 504 AN: 978

East Asian (EAS) AF: 0.602 AC: 1015 AN: 1686

South Asian (SAS) AF: 0.569 AC: 148 AN: 260

European-Finnish (FIN) AF: 0.552 AC: 570 AN: 1032

Middle Eastern (MID) AF: 0.402 AC: 41 AN: 102

European-Non Finnish (NFE) AF: 0.570 AC: 8622 AN: 15134

Other (OTH) AF: 0.590 AC: 994 AN: 1684

GnomAD4 genome AF: 0.455 AC: 69225 AN: 152054 Hom.: 16476 Cov.: 33 AF XY: 0.455 AC XY: 33808 AN XY: 74344

African (AFR) AF: 0.309 AC: 12825 AN: 41488

American (AMR) AF: 0.508 AC: 7759 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1597 AN: 3470

East Asian (EAS) AF: 0.538 AC: 2780 AN: 5170

South Asian (SAS) AF: 0.498 AC: 2402 AN: 4824

European-Finnish (FIN) AF: 0.475 AC: 5007 AN: 10546

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

European-Non Finnish (NFE) AF: 0.517 AC: 35150 AN: 67956

Other (OTH) AF: 0.449 AC: 949 AN: 2112

Alfa AF: 0.449 Hom.: 6018

Bravo AF: 0.457

Asia WGS AF: 0.483 AC: 1674 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		0.79
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: rs14240; hg19: chr10-119037071;