X-115610306-A-G

Variant names:

• chrX-115610306-A-G
• NM_005032.7:c.56A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005032.7(PLS3):​c.56A>G​(p.Glu19Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000973 in 1,027,916 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.7e-7 (0 hom. 0 hem.)
• Consequence: PLS3 NM_005032.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

Genes affected

PLS3 (HGNC:9091): (plastin 3) Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. Plastin 1 (otherwise known as Fimbrin) is a third distinct plastin isoform which is specifically expressed at high levels in the small intestine. The L isoform is expressed only in hemopoietic cell lineages, while the T isoform has been found in all other normal cells of solid tissues that have replicative potential (fibroblasts, endothelial cells, epithelial cells, melanocytes, etc.). The C-terminal 570 amino acids of the T-plastin and L-plastin proteins are 83% identical. It contains a potential calcium-binding site near the N terminus. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLS3	NM_005032.7	c.56A>G	p.Glu19Gly	missense_variant	Exon 2 of 16	ENST00000355899.8	NP_005023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLS3	ENST00000355899.8	c.56A>G	p.Glu19Gly	missense_variant	Exon 2 of 16	1	NM_005032.7	ENSP00000348163.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.73e-7 AC: 1 AN: 1027916 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 305680

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: 0.00

Gnomad4 OTH exome AF: 0.0000229

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56A>G (p.E19G) alteration is located in exon 2 (coding exon 1) of the PLS3 gene. This alteration results from a A to G substitution at nucleotide position 56, causing the glutamic acid (E) at amino acid position 19 to be replaced by a glycine (G). 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	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.041	T;D;D;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.5	.;M;M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.8	.;D;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.021	.;D;.;.
Sift4G	Uncertain	0.040	.;D;D;T
Polyphen		0.64	.;P;P;.
Vest4		0.59
MutPred		0.55		Loss of methylation at K23 (P = 0.0575);Loss of methylation at K23 (P = 0.0575);Loss of methylation at K23 (P = 0.0575);Loss of methylation at K23 (P = 0.0575);
MVP		0.85
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.61
gMVP		0.70

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: chrX-114844618;