19-40355817-A-C

Variant names:

• chr19-40355817-A-C
• rs4490097
• NM_012268.4:c.-279+7049A>C

Variant summary

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

The NM_012268.4(PLD3):​c.-279+7049A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 151,784 control chromosomes in the GnomAD database, including 12,131 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 0.37 (12126 hom., cov: 29)
  • Exomes 𝑓: 0.58 (5 hom.)
• Consequence: PLD3 NM_012268.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• Publications: 13 publications found

Genes affected

PLD3 (HGNC:17158): (phospholipase D family member 3) This gene encodes a member of the phospholipase D (PLD) family of enzymes that catalyze the hydrolysis of membrane phospholipids. The encoded protein is a single-pass type II membrane protein and contains two PLD phosphodiesterase domains. This protein influences processing of amyloid-beta precursor protein. Mutations in this gene are associated with Alzheimer disease risk. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Apr 2014]

PLD3 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 46

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000279759 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012268.4. 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
	PLD3	NM_012268.4	MANE Select	c.-279+7049A>C		intron	N/A	NP_036400.2
	PLD3	NM_001031696.4		c.-99+7093A>C		intron	N/A	NP_001026866.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLD3	ENST00000409735.9	TSL:1 MANE Select	c.-279+7049A>C		intron	N/A	ENSP00000386938.3
	PLD3	ENST00000356508.9	TSL:1	c.-99+7093A>C		intron	N/A	ENSP00000348901.5
	PLD3	ENST00000409419.5	TSL:5	c.-101+7049A>C		intron	N/A	ENSP00000386293.1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56655 AN: 151640 Hom.: 12129 Cov.: 29

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.577 AC: 15 AN: 26 Hom.: 5 Cov.: 0 AF XY: 0.545 AC XY: 12 AN XY: 22

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.750 AC: 3 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.611 AC: 11 AN: 18

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.373 AC: 56661 AN: 151758 Hom.: 12126 Cov.: 29 AF XY: 0.375 AC XY: 27805 AN XY: 74114

African (AFR) AF: 0.155 AC: 6439 AN: 41464

American (AMR) AF: 0.496 AC: 7539 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1323 AN: 3470

East Asian (EAS) AF: 0.493 AC: 2536 AN: 5142

South Asian (SAS) AF: 0.619 AC: 2975 AN: 4808

European-Finnish (FIN) AF: 0.379 AC: 3984 AN: 10506

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.451 AC: 30637 AN: 67858

Other (OTH) AF: 0.396 AC: 835 AN: 2110

Alfa AF: 0.419 Hom.: 18095

Bravo AF: 0.371

Asia WGS AF: 0.529 AC: 1837 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.2
DANN	Benign	0.70
PhyloP100		0.37
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: rs4490097; hg19: chr19-40861724; COSMIC: COSV62924932; COSMIC: COSV62924932;