X-115610944-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0650

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 -14 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_single_submitter, 1 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 GnomAd at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLS3	NM_005032.7	c.73+621C>A		intron_variant		ENST00000355899.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLS3	ENST00000355899.8	c.73+621C>A		intron_variant		1	NM_005032.7	P1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 1665 AN: 110751 Hom.: 23 Cov.: 24 AF XY: 0.0130 AC XY: 430 AN XY: 33023

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.: 4 AF XY: 0.00266 AC XY: 72 AN XY: 27071

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.: 23 Cov.: 11 AF XY: 0.00281 AC XY: 520 AN XY: 185184

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.: 23 Cov.: 24 AF XY: 0.0131 AC XY: 432 AN XY: 33089

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.: 93

Bravo AF: 0.0173

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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. -

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

Other links and lift over

dbSNP: rs5987754; hg19: chrX-114845256;