NM_178836.4:c.293T>A

Variant names:

• chr17-17205994-A-T
• rs375574430
• NM_178836.4:c.293T>A

Variant summary

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

The NM_178836.4(PLD6):​c.293T>A​(p.Leu98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L98R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PLD6 NM_178836.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81
• Publications: 0 publications found

Genes affected

PLD6 (HGNC:30447): (phospholipase D family member 6) Enables cardiolipin hydrolase activity and protein homodimerization activity. Involved in mitochondrial fusion. Acts upstream of or within positive regulation of mitochondrial fusion. Located in mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000264187 (HGNC:):

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178836.4. 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
	PLD6	NM_178836.4	MANE Select	c.293T>A	p.Leu98Gln	missense	Exon 1 of 2	NP_849158.2	Q8N2A8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLD6	ENST00000321560.4	TSL:1 MANE Select	c.293T>A	p.Leu98Gln	missense	Exon 1 of 2	ENSP00000317177.3	Q8N2A8
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*417+1031T>A		intron	N/A	ENSP00000394249.3	J3QW42
	MPRIP	ENST00000578209.5	TSL:3	c.*17+4361A>T		intron	N/A	ENSP00000464276.1	J3QRL2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 145754 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399510 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691190

African (AFR) AF: 0.0000313 AC: 1 AN: 31932

American (AMR) AF: 0.00 AC: 0 AN: 36458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 36258

South Asian (SAS) AF: 0.00 AC: 0 AN: 79652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082724

Other (OTH) AF: 0.00 AC: 0 AN: 58162

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.80	P
Vest4		0.74
MutPred		0.53		Loss of catalytic residue at L98 (P = 0.0057)
MVP		0.30
MPC		1.5
ClinPred		0.93	D
GERP RS		4.3
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375574430; hg19: chr17-17109308;