rs397518421

Variant names:

• chrX-115646495-C-T
• rs397518421
• NM_005032.7:c.1471C>T
• PLS3 p.Gln491*

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005032.7(PLS3):​c.1471C>T​(p.Gln491*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PLS3 NM_005032.7 stop_gained
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 3.25
• Publications: 3 publications found

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]

PLS3 Gene-Disease associations (from GenCC):

• X-linked osteoporosis with fractures

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hernia, anterior diaphragmatic

  Inheritance: XL Classification: MODERATE Submitted by: Baylor College of Medicine Research Center

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005032.7. 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
	PLS3	NM_005032.7	MANE Select	c.1471C>T	p.Gln491*	stop_gained	Exon 13 of 16	NP_005023.2
	PLS3	NM_001136025.5		c.1471C>T	p.Gln491*	stop_gained	Exon 13 of 16	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.1471C>T	p.Gln491*	stop_gained	Exon 14 of 17	NP_001427720.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLS3	ENST00000355899.8	TSL:1 MANE Select	c.1471C>T	p.Gln491*	stop_gained	Exon 13 of 16	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.1471C>T	p.Gln491*	stop_gained	Exon 13 of 16	ENSP00000445339.2	P13797-1
	PLS3	ENST00000969759.1		c.1519C>T	p.Gln507*	stop_gained	Exon 14 of 17	ENSP00000639818.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Bone mineral density quantitative trait locus 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		3.3
Mutation Taster		=0/200	disease causing (fs/PTC)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397518421;

hg19: chrX-114880815;