17-7390432-A-G

Position:

chr17-7390432-A-G

Variant summary

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

The NM_020360.4(PLSCR3):c.841T>C(p.Phe281Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000127 in 1,578,830 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PLSCR3
NM_020360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.94

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, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLSCR3	NM_020360.4 linkuse as main transcript	c.841T>C	p.Phe281Leu	missense_variant	8/8	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.841T>C	p.Phe281Leu	missense_variant	8/8	5	NM_020360.4	ENSP00000483743.2	Q9NRY6
TMEM256-PLSCR3	ENST00000573331.5 linkuse as main transcript	n.*1639T>C		non_coding_transcript_exon_variant	11/11	2		ENSP00000466104.1	K7ERE1
TMEM256-PLSCR3	ENST00000573331.5 linkuse as main transcript	n.*1639T>C		3_prime_UTR_variant	11/11	2		ENSP00000466104.1	K7ERE1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000104

AC:

AN:

192600

Hom.:

AF XY:

0.00000965

AC XY:

AN XY:

103588

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000142

Gnomad SAS 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:

7.01e-7

AC:

AN:

1426536

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000264

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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 17, 2021

The c.841T>C (p.F281L) alteration is located in exon 8 (coding exon 7) of the PLSCR3 gene. This alteration results from a T to C substitution at nucleotide position 841, causing the phenylalanine (F) at amino acid position 281 to be replaced by a leucine (L). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;T;T;.;.

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;M;M;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.5

D;D;.;.;.;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

D;D;.;.;.;.

Sift4G

Benign

0.063

T;T;T;T;D;D

Polyphen

0.12

B;B;B;B;.;.

Vest4

0.55

MutPred

0.81

Gain of ubiquitination at K284 (P = 0.2033);Gain of ubiquitination at K284 (P = 0.2033);Gain of ubiquitination at K284 (P = 0.2033);Gain of ubiquitination at K284 (P = 0.2033);.;.;

MVP

0.38

MPC

0.74

ClinPred

0.97

GERP RS

5.4

Varity_R

0.79

gMVP

0.46

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