Genetic Variant PLPP6:p.Ala48Val (chr9-4662518-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_203453.5(PLPP6):c.143C>T(p.Ala48Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A48G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PLPP6
NM_203453.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.488

Variant links:

Genes affected

PLPP6 (HGNC:23682): (phospholipid phosphatase 6) Enables lipid phosphatase activity. Involved in phospholipid dephosphorylation. Predicted to be located in plasma membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

PLPP6 links:

SPATA6L (HGNC:25472): (spermatogenesis associated 6 like) Predicted to enable myosin light chain binding activity. Predicted to be involved in spermatogenesis. Predicted to be located in sperm connecting piece. [provided by Alliance of Genome Resources, Apr 2022]

SPATA6L links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021105379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPP6	NM_203453.5 link	c.143C>T	p.Ala48Val	missense_variant	Exon 1 of 1	ENST00000381883.5	NP_982278.3	Q8IY26
SPATA6L	NM_001353486.2 link	c.40-482G>A		intron_variant	Intron 1 of 11	ENST00000682582.1	NP_001340415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLPP6	ENST00000381883.5 link	c.143C>T	p.Ala48Val	missense_variant	Exon 1 of 1	6	NM_203453.5	ENSP00000371307.2		Q8IY26
SPATA6L	ENST00000682582.1 link	c.40-482G>A		intron_variant	Intron 1 of 11		NM_001353486.2	ENSP00000506787.1		Q8N4H0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000570

AC:

AN:

175466

AF XY:

0.00

show subpopulations

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:

0.000124

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1408874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32274

American (AMR)

AF:

0.00

AC:

AN:

39724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24192

East Asian (EAS)

AF:

0.00

AC:

AN:

38380

South Asian (SAS)

AF:

0.00

AC:

AN:

80340

European-Finnish (FIN)

AF:

0.0000275

AC:

AN:

36354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4176

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094884

Other (OTH)

AF:

0.00

AC:

AN:

58550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000877

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0014

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.49

M_CAP

Benign

0.0083

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.96

PhyloP100

0.49

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.50

REVEL

Benign

0.018

Sift

Benign

0.29

Sift4G

Benign

0.29

Polyphen

0.0080

Vest4

0.026

MutPred

0.13

Gain of MoRF binding (P = 0.1631);

MVP

0.11

MPC

0.38

ClinPred

0.033

GERP RS

-2.7

PromoterAI

0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.041

gMVP

0.28

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over