rs140121121

chrX-115629281-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005032.7(PLS3):c.321T>A(p.Gly107=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.768

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 88702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-115629281-T-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLS3	NM_005032.7	c.321T>A	p.Gly107=	synonymous_variant	4/16	ENST00000355899.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLS3	ENST00000355899.8	c.321T>A	p.Gly107=	synonymous_variant	4/16	1	NM_005032.7	P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1381 AN: 111891 Hom.: 4 Cov.: 23 AF XY: 0.0123 AC XY: 419 AN XY: 34059

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

GnomAD3 exomes AF: 0.0147 AC: 2660 AN: 180425 Hom.: 36 AF XY: 0.0149 AC XY: 968 AN XY: 64991

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 SAS exome AF: 0.00627

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.: 27 AF XY: 0.0164 AC XY: 5876 AN XY: 358179

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00220

Gnomad4 ASJ exome AF: 0.00502

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00766

Gnomad4 FIN exome AF: 0.0500

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0123 AC: 1382 AN: 111942 Hom.: 4 Cov.: 23 AF XY: 0.0123 AC XY: 420 AN XY: 34120

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00326

Gnomad4 ASJ AF: 0.00677

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00450

Gnomad4 FIN AF: 0.0436

Gnomad4 NFE AF: 0.0184

Gnomad4 OTH AF: 0.0124

Alfa AF: 0.0152 Hom.: 113

Bravo AF: 0.00889

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bone mineral density quantitative trait locus 18 Benign:1 Other:1

association, no assertion criteria provided	literature only	OMIM	Oct 17, 2013	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 03, 2022

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	6.7
Dann	Benign	0.62

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

LitVar

Other links and lift over

dbSNP: rs140121121; hg19: chrX-114863593;