X-115622116-T-A

Variant names:

• chrX-115622116-T-A
• rs113228979
• NM_005032.7:c.74-130T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005032.7(PLS3):​c.74-130T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00555 in 519,785 control chromosomes in the GnomAD database, including 58 homozygotes. There are 760 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (42 hom., 538 hem., cov: 24)
  • Exomes 𝑓: 0.0024 (16 hom. 222 hem.)
• Consequence: PLS3 NM_005032.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.55
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-115622116-T-A is Benign according to our data. Variant chrX-115622116-T-A is described in ClinVar as Benign. ClinVar VariationId is 1287469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0542 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.74-130T>A		intron	N/A	NP_005023.2
	PLS3	NM_001136025.5		c.74-130T>A		intron	N/A	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.74-130T>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.74-130T>A		intron	N/A	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.74-130T>A		intron	N/A	ENSP00000445339.2	P13797-1
	PLS3	ENST00000489283.5	TSL:1	n.*327-130T>A		intron	N/A	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 1914 AN: 112105 Hom.: 42 Cov.: 24

Gnomad AFR AF: 0.0564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.0119

GnomAD4 exome AF: 0.00238 AC: 971 AN: 407628 Hom.: 16 Cov.: 6 AF XY: 0.00182 AC XY: 222 AN XY: 121696

African (AFR) AF: 0.0604 AC: 627 AN: 10387

American (AMR) AF: 0.00759 AC: 91 AN: 11994

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 19 AN: 12063

East Asian (EAS) AF: 0.00 AC: 0 AN: 22810

South Asian (SAS) AF: 0.000348 AC: 9 AN: 25895

European-Finnish (FIN) AF: 0.0000283 AC: 1 AN: 35330

Middle Eastern (MID) AF: 0.00361 AC: 6 AN: 1664

European-Non Finnish (NFE) AF: 0.000328 AC: 87 AN: 265398

Other (OTH) AF: 0.00593 AC: 131 AN: 22087

GnomAD4 genome AF: 0.0171 AC: 1916 AN: 112157 Hom.: 42 Cov.: 24 AF XY: 0.0157 AC XY: 538 AN XY: 34363

African (AFR) AF: 0.0564 AC: 1742 AN: 30909

American (AMR) AF: 0.0121 AC: 127 AN: 10523

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 7 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3581

South Asian (SAS) AF: 0.00 AC: 0 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6081

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000413 AC: 22 AN: 53278

Other (OTH) AF: 0.0118 AC: 18 AN: 1527

Alfa AF: 0.0135 Hom.: 42

Bravo AF: 0.0209

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.8
DANN	Benign	0.71
PhyloP100		1.6
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: rs113228979; hg19: chrX-114856428;