X-115610269-A-G

Variant names:

• chrX-115610269-A-G
• rs2074535390
• NM_005032.7:c.19A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005032.7(PLS3):​c.19A>G​(p.Thr7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PLS3 NM_005032.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078371376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLS3	NM_005032.7	c.19A>G	p.Thr7Ala	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.19A>G	p.Thr7Ala	missense_variant	Exon 2 of 16	1	NM_005032.7	ENSP00000348163.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1051141 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 327471

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: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19A>G (p.T7A) 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 19, causing the threonine (T) at amino acid position 7 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	0.058
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.033	T;T;T;.
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.67	T;.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.078	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.15	.;N;N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.18	.;N;.;.
REVEL	Benign	0.096
Sift	Benign	0.83	.;T;.;.
Sift4G	Benign	0.84	.;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.22
MutPred		0.18		Loss of glycosylation at T7 (P = 0.036);Loss of glycosylation at T7 (P = 0.036);Loss of glycosylation at T7 (P = 0.036);Loss of glycosylation at T7 (P = 0.036);
MVP		0.68
ClinPred		0.061	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.044
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs2074535390; hg19: chrX-114844581;