17-17205994-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_178836.4(PLD6):​c.293T>G​(p.Leu98Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,551,714 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: PLD6 NM_178836.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

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>G	p.Leu98Arg	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>G	p.Leu98Arg	missense	Exon 1 of 2	ENSP00000317177.3	Q8N2A8
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*417+1031T>G		intron	N/A	ENSP00000394249.3	J3QW42
	MPRIP	ENST00000578209.5	TSL:3	c.*17+4361A>C		intron	N/A	ENSP00000464276.1	J3QRL2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000632

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000110 AC: 16 AN: 145754 AF XY: 0.000113

Gnomad AFR exome AF: 0.000136

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: 0.000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000437 AC: 611 AN: 1399510 Hom.: 1 Cov.: 32 AF XY: 0.000411 AC XY: 284 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: 0.000526 AC: 570 AN: 1082724

Other (OTH) AF: 0.000688 AC: 40 AN: 58162

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74348

African (AFR) AF: 0.000121 AC: 5 AN: 41462

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000466 Hom.: 0

Bravo AF: 0.000261

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000454 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.89
MVP		0.37
MPC		1.8
ClinPred		0.26	T
GERP RS		4.3
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.93
Mutation Taster		=36/64	disease causing

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: rs375574430; hg19: chr17-17109308; COSMIC: COSV58634415;