chr19-40366633-C-T

Variant names:

• chr19-40366633-C-T
• rs200094590
• NM_012268.4:c.51C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_012268.4(PLD3):​c.51C>T​(p.Pro17Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,580,808 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: PLD3 NM_012268.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.68
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-40366633-C-T is Benign according to our data. Variant chr19-40366633-C-T is described in ClinVar as Benign. ClinVar VariationId is 2046284.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.68 with no splicing effect.
• BS2: High AC in GnomAd4 at 159 AD gene.

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.51C>T	p.Pro17Pro	synonymous	Exon 4 of 13	NP_036400.2	Q8IV08
	PLD3	NM_001031696.4		c.51C>T	p.Pro17Pro	synonymous	Exon 4 of 13	NP_001026866.1	Q8IV08
	PLD3	NM_001291311.2		c.51C>T	p.Pro17Pro	synonymous	Exon 4 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.51C>T	p.Pro17Pro	synonymous	Exon 4 of 13	ENSP00000386938.3	Q8IV08
	PLD3	ENST00000356508.9	TSL:1	c.51C>T	p.Pro17Pro	synonymous	Exon 4 of 13	ENSP00000348901.5	Q8IV08
	PLD3	ENST00000464586.1	TSL:1	n.242C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00970

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00158 AC: 355 AN: 225220 AF XY: 0.00120

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000974

Gnomad OTH exome AF: 0.000937

GnomAD4 exome AF: 0.000288 AC: 412 AN: 1428554 Hom.: 3 Cov.: 31 AF XY: 0.000247 AC XY: 175 AN XY: 707252

African (AFR) AF: 0.0000613 AC: 2 AN: 32642

American (AMR) AF: 0.00961 AC: 393 AN: 40888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23594

East Asian (EAS) AF: 0.00 AC: 0 AN: 39392

South Asian (SAS) AF: 0.00 AC: 0 AN: 81702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.00000457 AC: 5 AN: 1093814

Other (OTH) AF: 0.000204 AC: 12 AN: 58842

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74436

African (AFR) AF: 0.000120 AC: 5 AN: 41554

American (AMR) AF: 0.00975 AC: 149 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000379 Hom.: 1

Bravo AF: 0.00138

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.91
DANN	Benign	0.76
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs200094590; hg19: chr19-40872540; COSMIC: COSV100735349; COSMIC: COSV100735349;