17-7393188-G-C

Position:

• chr17-7393188-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020360.4(PLSCR3):​c.463C>G​(p.Pro155Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000146 in 1,370,368 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: 0.0000015 (0 hom.)
• Consequence: PLSCR3 NM_020360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

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]

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]

PLSCR3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLSCR3	NM_020360.4	c.463C>G	p.Pro155Ala	missense_variant	5/8	ENST00000619711.5	NP_065093.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLSCR3	ENST00000619711.5	c.463C>G	p.Pro155Ala	missense_variant	5/8	5	NM_020360.4	ENSP00000483743.2
TMEM256-PLSCR3	ENST00000573331.5	n.*1261C>G		non_coding_transcript_exon_variant	8/11	2		ENSP00000466104.1
TMEM256-PLSCR3	ENST00000573331.5	n.*1261C>G		3_prime_UTR_variant	8/11	2		ENSP00000466104.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1370368 Hom.: 0 Cov.: 36 AF XY: 0.00000148 AC XY: 1 AN XY: 676590

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: 0.00000186

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

Nov 12, 2021

The c.463C>G (p.P155A) alteration is located in exon 5 (coding exon 4) of the PLSCR3 gene. This alteration results from a C to G substitution at nucleotide position 463, causing the proline (P) at amino acid position 155 to be replaced by an alanine (A). 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	0.31
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T;T;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;M;M;M;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.8	D;D;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.075	T;T;.;.;.;.
Sift4G	Benign	0.085	T;T;T;T;D;T
Polyphen		0.95	P;P;P;P;.;.
Vest4		0.58
MutPred		0.84		Loss of disorder (P = 0.0608);Loss of disorder (P = 0.0608);Loss of disorder (P = 0.0608);Loss of disorder (P = 0.0608);Loss of disorder (P = 0.0608);.;
MVP		0.60
MPC		1.4
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.47
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7296507;