rs10521693

Variant names:

• chrX-115566179-A-C
• rs10521693
• NM_005032.7:c.-9+4919A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005032.7(PLS3):​c.-9+4919A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 112,168 control chromosomes in the GnomAD database, including 30 homozygotes. There are 804 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 0.024 (30 hom., 804 hem., cov: 24)
• Consequence: PLS3 NM_005032.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.17
• Publications: 1 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: Ambry Genetics, G2P, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0245 (2745/112168) while in subpopulation SAS AF = 0.0502 (135/2689). AF 95% confidence interval is 0.0433. There are 30 homozygotes in GnomAd4. There are 804 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLS3	NM_005032.7	c.-9+4919A>C		intron_variant	Intron 1 of 15	ENST00000355899.8	NP_005023.2
PLS3	NM_001282337.2	c.-194+4919A>C		intron_variant	Intron 1 of 17		NP_001269266.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLS3	ENST00000355899.8	c.-9+4919A>C		intron_variant	Intron 1 of 15	1	NM_005032.7	ENSP00000348163.3
PLS3	ENST00000489283.5	n.-9+4919A>C		intron_variant	Intron 1 of 5	1		ENSP00000420458.1
PLS3	ENST00000289290.7	c.-194+4919A>C		intron_variant	Intron 1 of 17	2		ENSP00000289290.4
PLS3	ENST00000626746.2	c.-9+4919A>C		intron_variant	Intron 1 of 2	4		ENSP00000487343.1

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 2744 AN: 112115 Hom.: 30 Cov.: 24

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.0146

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0557

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.0489

Gnomad FIN AF: 0.00772

Gnomad MID AF: 0.0458

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0290

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

GnomAD4 genome AF: 0.0245 AC: 2745 AN: 112168 Hom.: 30 Cov.: 24 AF XY: 0.0234 AC XY: 804 AN XY: 34334

African (AFR) AF: 0.0362 AC: 1120 AN: 30922

American (AMR) AF: 0.0324 AC: 342 AN: 10571

Ashkenazi Jewish (ASJ) AF: 0.0557 AC: 148 AN: 2658

East Asian (EAS) AF: 0.0284 AC: 101 AN: 3562

South Asian (SAS) AF: 0.0502 AC: 135 AN: 2689

European-Finnish (FIN) AF: 0.00772 AC: 47 AN: 6086

Middle Eastern (MID) AF: 0.0411 AC: 9 AN: 219

European-Non Finnish (NFE) AF: 0.0148 AC: 789 AN: 53240

Other (OTH) AF: 0.0287 AC: 44 AN: 1535

Alfa AF: 0.0185 Hom.: 98

Bravo AF: 0.0292

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.6
DANN	Benign	0.63
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10521693; hg19: chrX-114800505;