Genetic Variant NM_005032.7:c.74-50C>A (chrX-115622196-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005032.7(PLS3):c.74-50C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00816 in 1,024,046 control chromosomes in the GnomAD database, including 372 homozygotes. There are 2,219 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 209 hom., 1132 hem., cov: 23)

Exomes 𝑓: 0.0045 ( 163 hom. 1087 hem. )

Consequence

PLS3
NM_005032.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.52

Publications

0 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant X-115622196-C-A is Benign according to our data. Variant chrX-115622196-C-A is described in ClinVar as Benign. ClinVar VariationId is 1243943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PLS3	NM_005032.7	MANE Select	c.74-50C>A	intron	N/A	NP_005023.2
PLS3	NM_001136025.5		c.74-50C>A	intron	N/A	NP_001129497.1	P13797-1
PLS3	NM_001440791.1		c.74-50C>A	intron	N/A	NP_001427720.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PLS3	ENST00000355899.8	TSL:1 MANE Select	c.74-50C>A	intron	N/A	ENSP00000348163.3	P13797-1
PLS3	ENST00000539310.5	TSL:1	c.74-50C>A	intron	N/A	ENSP00000445339.2	P13797-1
PLS3	ENST00000489283.5	TSL:1	n.*327-50C>A	intron	N/A	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes

AF:

0.0380

AC:

4245

AN:

111812

Hom.:

209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.00151

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00404

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.0286

GnomAD2 exomes

AF:

0.0121

AC:

1875

AN:

155553

AF XY:

0.00794

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.00677

Gnomad ASJ exome

AF:

0.00287

Gnomad EAS exome

AF:

0.0000852

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000402

Gnomad OTH exome

AF:

0.00655

GnomAD4 exome

AF:

0.00449

AC:

4098

AN:

912182

Hom.:

163

Cov.:

AF XY:

0.00422

AC XY:

1087

AN XY:

257328

show subpopulations

African (AFR)

AF:

0.141

AC:

3092

AN:

21977

American (AMR)

AF:

0.00835

AC:

245

AN:

29353

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

17814

East Asian (EAS)

AF:

0.00

AC:

AN:

28976

South Asian (SAS)

AF:

0.00429

AC:

193

AN:

44976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40256

Middle Eastern (MID)

AF:

0.00547

AC:

AN:

3657

European-Non Finnish (NFE)

AF:

0.000198

AC:

136

AN:

685482

Other (OTH)

AF:

0.00947

AC:

376

AN:

39691

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

129

259

388

518

647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.0381

AC:

4260

AN:

111864

Hom.:

209

Cov.:

AF XY:

0.0332

AC XY:

1132

AN XY:

34054

show subpopulations

African (AFR)

AF:

0.131

AC:

4032

AN:

30748

American (AMR)

AF:

0.0149

AC:

156

AN:

10481

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3591

South Asian (SAS)

AF:

0.00368

AC:

AN:

2718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6027

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000207

AC:

AN:

53223

Other (OTH)

AF:

0.0302

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

137

274

412

549

686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0201

Hom.:

106

Bravo

AF:

0.0443

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.011

(source)

DANN

Benign

0.44

PhyloP100

-1.5

Mutation Taster

=100/0

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

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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

Computational scores

Splicing

Publications

Other links and lift over