3-146201067-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020353.3(PLSCR4):c.365T>C(p.Ile122Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,401,160 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLSCR4 NM_020353.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34

Genes affected

PLSCR4 (HGNC:16497): (phospholipid scramblase 4) Enables CD4 receptor binding activity and enzyme binding activity. Predicted to be involved in plasma membrane phospholipid scrambling. Predicted to act upstream of or within cellular response to lipopolysaccharide. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLSCR4	NM_020353.3	c.365T>C	p.Ile122Thr	missense_variant	5/9	ENST00000354952.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLSCR4	ENST00000354952.7	c.365T>C	p.Ile122Thr	missense_variant	5/9	1	NM_020353.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1401160 Hom.: 0 Cov.: 27 AF XY: 0.00000287 AC XY: 2 AN XY: 696080

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

The c.365T>C (p.I122T) alteration is located in exon 5 (coding exon 4) of the PLSCR4 gene. This alteration results from a T to C substitution at nucleotide position 365, causing the isoleucine (I) at amino acid position 122 to be replaced by a threonine (T). 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	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.095	T;T;T;T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.1	M;M;M;.;.;.
MutationTaster	Benign	0.81	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.013	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.
Polyphen		0.96	D;D;D;.;.;.
Vest4		0.81
MutPred		0.74		Loss of stability (P = 3e-04);Loss of stability (P = 3e-04);Loss of stability (P = 3e-04);Loss of stability (P = 3e-04);Loss of stability (P = 3e-04);Loss of stability (P = 3e-04);
MVP		0.35
MPC		0.42
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-145918854;