3-146201064-T-G

Variant names:

• chr3-146201064-T-G
• rs761519089
• NM_020353.3:c.368A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020353.3(PLSCR4):​c.368A>C​(p.His123Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,401,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. H123R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLSCR4 NM_020353.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3957022).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020353.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLSCR4	NM_020353.3	MANE Select	c.368A>C	p.His123Pro	missense	Exon 5 of 9	NP_065086.2	Q9NRQ2-1
	PLSCR4	NM_001128304.2		c.368A>C	p.His123Pro	missense	Exon 7 of 11	NP_001121776.1	Q9NRQ2-1
	PLSCR4	NM_001128305.2		c.368A>C	p.His123Pro	missense	Exon 5 of 9	NP_001121777.1	Q9NRQ2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLSCR4	ENST00000354952.7	TSL:1 MANE Select	c.368A>C	p.His123Pro	missense	Exon 5 of 9	ENSP00000347038.2	Q9NRQ2-1
	PLSCR4	ENST00000446574.6	TSL:2	c.368A>C	p.His123Pro	missense	Exon 5 of 9	ENSP00000399315.2	Q9NRQ2-1
	PLSCR4	ENST00000493382.5	TSL:2	c.368A>C	p.His123Pro	missense	Exon 7 of 11	ENSP00000419040.1	Q9NRQ2-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1401876 Hom.: 0 Cov.: 27 AF XY: 0.00000144 AC XY: 1 AN XY: 696378

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

African (AFR) AF: 0.0000678 AC: 2 AN: 29496

American (AMR) AF: 0.00 AC: 0 AN: 30822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24490

East Asian (EAS) AF: 0.00 AC: 0 AN: 36334

South Asian (SAS) AF: 0.00 AC: 0 AN: 74652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089480

Other (OTH) AF: 0.00 AC: 0 AN: 58018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.97	D
Vest4		0.61
MutPred		0.58		Gain of sheet (P = 0.1208)
MVP		0.30
MPC		0.39
ClinPred		0.85	D
GERP RS		4.0
Varity_R		0.71
gMVP		0.76
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs761519089; hg19: chr3-145918851;