NM_005032.7:c.-8-139G>A

Variant names:

• chrX-115610104-G-A
• rs73581642
• NM_005032.7:c.-8-139G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005032.7(PLS3):​c.-8-139G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00723 in 305,013 control chromosomes in the GnomAD database, including 35 homozygotes. There are 622 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (33 hom., 500 hem., cov: 23)
  • Exomes 𝑓: 0.0024 (2 hom. 122 hem.)
• Consequence: PLS3 NM_005032.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.857
• 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, 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-115610104-G-A is Benign according to our data. Variant chrX-115610104-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1196403.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 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.-8-139G>A		intron	N/A	NP_005023.2
	PLS3	NM_001136025.5		c.-8-139G>A		intron	N/A	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.-8-139G>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.-8-139G>A		intron	N/A	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.-8-139G>A		intron	N/A	ENSP00000445339.2	P13797-1
	PLS3	ENST00000489283.5	TSL:1	n.-8-139G>A		intron	N/A	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 1731 AN: 112098 Hom.: 33 Cov.: 23

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000367

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.000320

Gnomad OTH AF: 0.0112

GnomAD4 exome AF: 0.00244 AC: 470 AN: 192860 Hom.: 2 AF XY: 0.00215 AC XY: 122 AN XY: 56820

African (AFR) AF: 0.0544 AC: 308 AN: 5658

American (AMR) AF: 0.00488 AC: 28 AN: 5737

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6681

East Asian (EAS) AF: 0.00 AC: 0 AN: 16892

South Asian (SAS) AF: 0.000873 AC: 3 AN: 3436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19656

Middle Eastern (MID) AF: 0.00768 AC: 7 AN: 912

European-Non Finnish (NFE) AF: 0.000380 AC: 46 AN: 121096

Other (OTH) AF: 0.00610 AC: 78 AN: 12792

GnomAD4 genome AF: 0.0155 AC: 1735 AN: 112153 Hom.: 33 Cov.: 23 AF XY: 0.0145 AC XY: 500 AN XY: 34365

African (AFR) AF: 0.0532 AC: 1646 AN: 30966

American (AMR) AF: 0.00484 AC: 51 AN: 10529

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3613

South Asian (SAS) AF: 0.000368 AC: 1 AN: 2714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6070

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.000320 AC: 17 AN: 53169

Other (OTH) AF: 0.0111 AC: 17 AN: 1533

Alfa AF: 0.0119 Hom.: 36

Bravo AF: 0.0180

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.19
DANN	Benign	0.20
PhyloP100		-0.86
PromoterAI		-0.0037	Neutral
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: rs73581642; hg19: chrX-114844416;