Genetic Variant PLSCR1:p.His12Tyr (chr3-146533530-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_021105.3(PLSCR1):c.34C>T(p.His12Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,452,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

PLSCR1
NM_021105.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0600

Variant links:

Genes affected

PLSCR1 (HGNC:9092): (phospholipid scramblase 1) This gene encodes a phospholipid scramblase family member. The encoded protein is involved in disruption of the asymmetrical distribution of phospholipids between the inner and outer leaflets of the plasma membrane, resulting in externalization of phosphatidylserine. This cell membrane disruption plays an important role in the blood coagulation cascade as well as macrophage clearing of apoptotic cells. The encoded protein has additionally been implicated in gene regulation and interferon-induced antiviral responses. [provided by RefSeq, May 2022]

PLSCR1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a mutagenesis_site 60% reduction in nuclease activity; when associated with A-53; A-111; A-211 and A-262. (size 0) in uniprot entity PLS1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03984353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLSCR1	NM_021105.3 link	c.34C>T	p.His12Tyr	missense_variant	Exon 3 of 9	ENST00000342435.9	NP_066928.1	O15162-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLSCR1	ENST00000342435.9 link	c.34C>T	p.His12Tyr	missense_variant	Exon 3 of 9	1	NM_021105.3	ENSP00000345494.4		O15162-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251376

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000688

AC:

AN:

1452834

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000905

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>T (p.H12Y) alteration is located in exon 3 (coding exon 2) of the PLSCR1 gene. This alteration results from a C to T substitution at nucleotide position 34, causing the histidine (H) at amino acid position 12 to be replaced by a tyrosine (Y). 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

Benign

0.061

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.42

DANN

Benign

0.60

DEOGEN2

Benign

0.057

T;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.64

T;T;T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.68

N;.;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.32

N;N;N;N

REVEL

Benign

0.023

Sift

Benign

0.47

T;T;T;T

Sift4G

Benign

1.0

T;T;.;.

Polyphen

0.0040

B;.;.;.

Vest4

0.16

MutPred

0.26

Gain of catalytic residue at H12 (P = 0.0413);.;Gain of catalytic residue at H12 (P = 0.0413);Gain of catalytic residue at H12 (P = 0.0413);

MVP

0.26

MPC

0.19

ClinPred

0.018

GERP RS

1.7

Varity_R

0.023

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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