17-7393206-C-T

Position:

chr17-7393206-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020360.4(PLSCR3):c.445G>A(p.Val149Met) variant causes a missense change. The variant allele was found at a frequency of 0.000224 in 1,554,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

PLSCR3
NM_020360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

Variant links:

Genes affected

PLSCR3 (HGNC:16495): (phospholipid scramblase 3) Enables several functions, including calcium-dependent protein binding activity; metal ion binding activity; and phospholipid scramblase activity. Involved in several processes, including cardiolipin biosynthetic process; regulation of apoptotic process; and regulation of release of cytochrome c from mitochondria. Located in cytosol; mitochondrion; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

PLSCR3 links:

TMEM256-PLSCR3 (HGNC:49186): (TMEM256-PLSCR3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring chromosome 17 open reading frame 61 (C17orf61) and phospholipid scramblase 3 (PLSCR3) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Jan 2011]

TMEM256-PLSCR3 links:

PLSCR3 (HGNC:):

PLSCR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.744

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLSCR3	NM_020360.4 linkuse as main transcript	c.445G>A	p.Val149Met	missense_variant	5/8	ENST00000619711.5	NP_065093.2	Q9NRY6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PLSCR3	ENST00000619711.5 linkuse as main transcript	c.445G>A	p.Val149Met	missense_variant	5/8	5	NM_020360.4	ENSP00000483743.2	Q9NRY6
TMEM256-PLSCR3	ENST00000573331.5 linkuse as main transcript	n.*1243G>A		non_coding_transcript_exon_variant	8/11	2		ENSP00000466104.1	K7ERE1
TMEM256-PLSCR3	ENST00000573331.5 linkuse as main transcript	n.*1243G>A		3_prime_UTR_variant	8/11	2		ENSP00000466104.1	K7ERE1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000181

AC:

AN:

165446

Hom.:

AF XY:

0.000150

AC XY:

AN XY:

93298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000227

AC:

318

AN:

1402598

Hom.:

Cov.:

AF XY:

0.000214

AC XY:

149

AN XY:

695500

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000287

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000162

Gnomad4 NFE exome

AF:

0.000277

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.000197

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000383

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000510

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.000118

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 15, 2021

The c.445G>A (p.V149M) alteration is located in exon 5 (coding exon 4) of the PLSCR3 gene. This alteration results from a G to A substitution at nucleotide position 445, causing the valine (V) at amino acid position 149 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.0088

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;T;T;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.74

D;D;D;D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Pathogenic

3.1

M;M;M;M;.;.

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.9

D;D;.;.;.;.

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;D;.;.;.;.

Sift4G

Uncertain

0.045

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;.;.

Vest4

0.66

MutPred

0.80

Gain of catalytic residue at V149 (P = 0.0297);Gain of catalytic residue at V149 (P = 0.0297);Gain of catalytic residue at V149 (P = 0.0297);Gain of catalytic residue at V149 (P = 0.0297);Gain of catalytic residue at V149 (P = 0.0297);.;

MVP

0.65

MPC

1.5

ClinPred

0.65

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over