rs397518463

Variant names:

• chrX-115622404-GT-G
• rs397518463
• NM_005032.7:c.235delT

Variant summary

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

The NM_005032.7(PLS3):​c.235delT​(p.Tyr79IlefsTer6) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as association (no stars). Synonymous variant affecting the same amino acid position (i.e. Y79Y) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PLS3 NM_005032.7 frameshift, splice_region
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 6.27
• Publications: 6 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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.235delT	p.Tyr79IlefsTer6	frameshift splice_region	Exon 3 of 16	NP_005023.2
	PLS3	NM_001136025.5		c.235delT	p.Tyr79IlefsTer6	frameshift splice_region	Exon 3 of 16	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.235delT	p.Tyr79IlefsTer6	frameshift splice_region	Exon 4 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.235delT	p.Tyr79IlefsTer6	frameshift splice_region	Exon 3 of 16	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.235delT	p.Tyr79IlefsTer6	frameshift splice_region	Exon 3 of 16	ENSP00000445339.2	P13797-1
	PLS3	ENST00000489283.5	TSL:1	n.*488delT		splice_region non_coding_transcript_exon	Exon 4 of 6	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 23

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
PhyloP100		6.3
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397518463;

hg19: chrX-114856716;