Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005032.7(PLS3):c.321T>A(p.Gly107Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,204,373 control chromosomes in the GnomAD database, including 145 homozygotes. There are 6,296 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 4 hom., 420 hem., cov: 23)

Exomes 𝑓: 0.017 ( 141 hom. 5876 hem. )

Consequence

PLS3
NM_005032.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.768

Publications

7 publications found

Variant links:

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
hernia, anterior diaphragmatic
Inheritance: XL Classification: MODERATE Submitted by: Baylor College of Medicine Research Center

PLS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant X-115629281-T-A is Benign according to our data. Variant chrX-115629281-T-A is described in ClinVar as Benign. ClinVar VariationId is 88702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.768 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0123 (1382/111942) while in subpopulation NFE AF = 0.0184 (982/53243). AF 95% confidence interval is 0.0175. There are 4 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLS3	NM_005032.7	MANE Select	c.321T>A	p.Gly107Gly	synonymous	Exon 4 of 16	NP_005023.2
PLS3	NM_001136025.5		c.321T>A	p.Gly107Gly	synonymous	Exon 4 of 16	NP_001129497.1
PLS3	NM_001440791.1		c.321T>A	p.Gly107Gly	synonymous	Exon 5 of 17	NP_001427720.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLS3	ENST00000355899.8	TSL:1 MANE Select	c.321T>A	p.Gly107Gly	synonymous	Exon 4 of 16	ENSP00000348163.3
PLS3	ENST00000539310.5	TSL:1	c.321T>A	p.Gly107Gly	synonymous	Exon 4 of 16	ENSP00000445339.2
PLS3	ENST00000489283.5	TSL:1	n.*574T>A		non_coding_transcript_exon	Exon 5 of 6	ENSP00000420458.1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1381

AN:

111891

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00326

Gnomad ASJ

AF:

0.00677

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00448

Gnomad FIN

AF:

0.0436

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.0184

Gnomad OTH

AF:

0.0126

GnomAD2 exomes

AF:

0.0147

AC:

2660

AN:

180425

AF XY:

0.0149

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00232

Gnomad ASJ exome

AF:

0.00471

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0524

Gnomad NFE exome

AF:

0.0190

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.0166

AC:

18125

AN:

1092431

Hom.:

141

Cov.:

AF XY:

0.0164

AC XY:

5876

AN XY:

358179

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

26260

American (AMR)

AF:

0.00220

AC:

AN:

34996

Ashkenazi Jewish (ASJ)

AF:

0.00502

AC:

AN:

19313

East Asian (EAS)

AF:

0.00

AC:

AN:

30105

South Asian (SAS)

AF:

0.00766

AC:

411

AN:

53656

European-Finnish (FIN)

AF:

0.0500

AC:

2025

AN:

40500

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0177

AC:

14849

AN:

837560

Other (OTH)

AF:

0.0132

AC:

607

AN:

45915

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

542

1085

1627

2170

2712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

536

1072

1608

2144

2680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0123

AC:

1382

AN:

111942

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

420

AN XY:

34120

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

30901

American (AMR)

AF:

0.00326

AC:

AN:

10435

Ashkenazi Jewish (ASJ)

AF:

0.00677

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3572

South Asian (SAS)

AF:

0.00450

AC:

AN:

2669

European-Finnish (FIN)

AF:

0.0436

AC:

263

AN:

6039

Middle Eastern (MID)

AF:

0.00930

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0184

AC:

982

AN:

53243

Other (OTH)

AF:

0.0124

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

142

189

236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0152

Hom.:

113

Bravo

AF:

0.00889

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Bone mineral density quantitative trait locus 18 (2)

not specified (1)

Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.7

(source)

DANN

Benign

0.62

PhyloP100

-0.77

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs140121121

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over