19-40366500-T-G

Variant names:

• chr19-40366500-T-G
• rs762406245
• NM_012268.4:c.17T>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_012268.4(PLD3):​c.17T>G​(p.Met6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PLD3 NM_012268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLD3	NM_012268.4	c.17T>G	p.Met6Arg	missense_variant	Exon 3 of 13	ENST00000409735.9	NP_036400.2
PLD3	NM_001031696.4	c.17T>G	p.Met6Arg	missense_variant	Exon 3 of 13		NP_001026866.1
PLD3	NM_001291311.2	c.17T>G	p.Met6Arg	missense_variant	Exon 3 of 13		NP_001278240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLD3	ENST00000409735.9	c.17T>G	p.Met6Arg	missense_variant	Exon 3 of 13	1	NM_012268.4	ENSP00000386938.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250832 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461546 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152010 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74242

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs762406245, gnomAD 0.004%). This missense change has been observed in individual(s) with Alzheimer's disease (PMID: 24336208). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 6 of the PLD3 protein (p.Met6Arg). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	.;T;T;T;T;T;T;T;T;T;.;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.0028
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.72	T;T;T;.;.;T;.;T;.;T;T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;.;L;L;.;L;.;L;.;.;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.42	.;N;.;N;N;.;N;.;N;.;.;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.11	.;T;.;T;T;.;T;.;T;.;.;T;T
Sift4G	Pathogenic	0.0	D;T;D;T;T;D;T;D;T;D;T;T;T
Polyphen		0.10	.;.;.;B;B;.;B;.;B;.;.;B;.
Vest4		0.66, 0.86, 0.67, 0.84
MVP		0.41
MPC		0.57
ClinPred		0.22	T
GERP RS		3.9
Varity_R		0.36
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762406245; hg19: chr19-40872407;