NM_012268.4:c.164C>G

Variant names:

• chr19-40366834-C-G
• rs977484313
• NM_012268.4:c.164C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012268.4(PLD3):​c.164C>G​(p.Thr55Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T55I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLD3 NM_012268.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00
• Publications: 1 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19043079).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLD3	NM_012268.4	MANE Select	c.164C>G	p.Thr55Ser	missense	Exon 5 of 13	NP_036400.2	Q8IV08
	PLD3	NM_001031696.4		c.164C>G	p.Thr55Ser	missense	Exon 5 of 13	NP_001026866.1	Q8IV08
	PLD3	NM_001291311.2		c.164C>G	p.Thr55Ser	missense	Exon 5 of 13	NP_001278240.1	Q8IV08

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLD3	ENST00000409735.9	TSL:1 MANE Select	c.164C>G	p.Thr55Ser	missense	Exon 5 of 13	ENSP00000386938.3	Q8IV08
	PLD3	ENST00000356508.9	TSL:1	c.164C>G	p.Thr55Ser	missense	Exon 5 of 13	ENSP00000348901.5	Q8IV08
	PLD3	ENST00000485448.1	TSL:1	n.298C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.98	L
PhyloP100		4.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.10
Sift	Benign	0.65	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.19	B
Vest4		0.57
MutPred		0.35		Gain of sheet (P = 0.0477)
MVP		0.58
MPC		0.34
ClinPred		0.43	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.47
Mutation Taster		=87/13	polymorphism

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: rs977484313; hg19: chr19-40872741;