Genetic Variant PLSCR5:p.Gly254Val (chr3-146589669-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001085420.2(PLSCR5):c.761G>T(p.Gly254Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G254D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PLSCR5
NM_001085420.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.85

Publications

0 publications found

Variant links:

Genes affected

PLSCR5 (HGNC:19952): (phospholipid scramblase family member 5) Predicted to enable phospholipid scramblase activity. Predicted to be involved in plasma membrane phospholipid scrambling. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

PLSCR5 links:

PLSCR5-AS1 (HGNC:40907): (PLSCR5 antisense RNA 1)

PLSCR5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085420.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLSCR5	NM_001085420.2	MANE Select	c.761G>T	p.Gly254Val	missense	Exon 6 of 8	NP_001078889.1	A0PG75-1
PLSCR5	NM_001321245.2		c.725G>T	p.Gly242Val	missense	Exon 6 of 8	NP_001308174.1	A0PG75-2
PLSCR5-AS1	NR_046698.1		n.68C>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLSCR5	ENST00000443512.2	TSL:1 MANE Select	c.761G>T	p.Gly254Val	missense	Exon 6 of 8	ENSP00000390111.1	A0PG75-1
PLSCR5	ENST00000482567.5	TSL:1	c.725G>T	p.Gly242Val	missense	Exon 6 of 8	ENSP00000418626.1	A0PG75-2
PLSCR5	ENST00000492200.5	TSL:5	c.761G>T	p.Gly254Val	missense	Exon 6 of 8	ENSP00000417184.1	A0PG75-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1435786

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713090

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32826

American (AMR)

AF:

0.00

AC:

AN:

42874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25394

East Asian (EAS)

AF:

0.00

AC:

AN:

39172

South Asian (SAS)

AF:

0.00

AC:

AN:

82674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095412

Other (OTH)

AF:

0.00

AC:

AN:

59148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.12

MutationAssessor

Pathogenic

3.1

PhyloP100

5.9

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-8.8

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.99

MutPred

0.87

Loss of loop (P = 0.0804)

MVP

0.59

MPC

0.0036

ClinPred

1.0

GERP RS

4.4

Varity_R

0.88

gMVP

0.90

Mutation Taster

=57/43

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over