X-115597455-G-A

Variant names:

• chrX-115597455-G-A
• rs6643869
• NM_005032.7:c.-8-12788G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005032.7(PLS3):​c.-8-12788G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 110,794 control chromosomes in the GnomAD database, including 4,234 homozygotes. There are 10,182 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (4234 hom., 10182 hem., cov: 23)
• Consequence: PLS3 NM_005032.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.297
• 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, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hernia, anterior diaphragmatic

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

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.-8-12788G>A		intron	N/A	NP_005023.2
	PLS3	NM_001136025.5		c.-9+3823G>A		intron	N/A	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.-84+3823G>A		intron	N/A	NP_001427720.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLS3	ENST00000355899.8	TSL:1 MANE Select	c.-8-12788G>A		intron	N/A	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.-9+3823G>A		intron	N/A	ENSP00000445339.2	P13797-1
	PLS3	ENST00000489283.5	TSL:1	n.-8-12788G>A		intron	N/A	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes AF: 0.301 AC: 33342 AN: 110738 Hom.: 4233 Cov.: 23

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.301 AC: 33337 AN: 110794 Hom.: 4234 Cov.: 23 AF XY: 0.308 AC XY: 10182 AN XY: 33038

African (AFR) AF: 0.0803 AC: 2464 AN: 30667

American (AMR) AF: 0.356 AC: 3693 AN: 10383

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 901 AN: 2629

East Asian (EAS) AF: 0.369 AC: 1286 AN: 3483

South Asian (SAS) AF: 0.458 AC: 1200 AN: 2618

European-Finnish (FIN) AF: 0.492 AC: 2823 AN: 5739

Middle Eastern (MID) AF: 0.247 AC: 53 AN: 215

European-Non Finnish (NFE) AF: 0.385 AC: 20355 AN: 52878

Other (OTH) AF: 0.296 AC: 443 AN: 1498

Alfa AF: 0.336 Hom.: 18234

Bravo AF: 0.281

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.55
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6643869; hg19: chrX-114831767;