Genetic Variant PLS3:c.73+621C>A (chrX-115610944-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005032.7(PLS3):c.73+621C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 809,967 control chromosomes in the GnomAD database, including 46 homozygotes. There are 952 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 ( 23 hom., 432 hem., cov: 24)

Exomes 𝑓: 0.0030 ( 23 hom. 520 hem. )

Consequence

PLS3
NM_005032.7 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0650

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant X-115610944-C-A is Benign according to our data. Variant chrX-115610944-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 676714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.015 (1667/110807) while in subpopulation AFR AF= 0.0477 (1457/30544). AF 95% confidence interval is 0.0457. There are 23 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLS3	NM_005032.7 link	c.73+621C>A		intron_variant	Intron 2 of 15	ENST00000355899.8	NP_005023.2	P13797-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLS3	ENST00000355899.8 link	c.73+621C>A		intron_variant	Intron 2 of 15	1	NM_005032.7	ENSP00000348163.3		P13797-1

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

1665

AN:

110751

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

430

AN XY:

33023

show subpopulations

Gnomad AFR

AF:

0.0477

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00937

Gnomad ASJ

AF:

0.00265

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000765

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0212

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.00452

AC:

381

AN:

84217

Hom.:

AF XY:

0.00266

AC XY:

AN XY:

27071

show subpopulations

Gnomad AFR exome

AF:

0.0509

Gnomad AMR exome

AF:

0.00491

Gnomad ASJ exome

AF:

0.00282

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.00826

GnomAD4 exome

AF:

0.00298

AC:

2085

AN:

699160

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

520

AN XY:

185184

show subpopulations

Gnomad4 AFR exome

AF:

0.0509

Gnomad4 AMR exome

AF:

0.00658

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000169

Gnomad4 FIN exome

AF:

0.0000790

Gnomad4 NFE exome

AF:

0.00127

Gnomad4 OTH exome

AF:

0.00753

GnomAD4 genome

AF:

0.0150

AC:

1667

AN:

110807

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

432

AN XY:

33089

show subpopulations

Gnomad4 AFR

AF:

0.0477

Gnomad4 AMR

AF:

0.00936

Gnomad4 ASJ

AF:

0.00265

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000767

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00148

Gnomad4 OTH

AF:

0.0141

Alfa

AF:

0.00524

Hom.:

Bravo

AF:

0.0173

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

7.3

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over