NM_005032.7:c.-8-20C>T

Variant names:

• chrX-115610223-C-T
• rs114186394
• NM_005032.7:c.-8-20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005032.7(PLS3):​c.-8-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 927,014 control chromosomes in the GnomAD database, including 231 homozygotes. There are 1,607 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (134 hom., 966 hem., cov: 23)
  • Exomes 𝑓: 0.0034 (97 hom. 641 hem.)
• Consequence: PLS3 NM_005032.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.25
• Publications: 0 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hernia, anterior diaphragmatic

  Inheritance: XL Classification: MODERATE Submitted by: Baylor College of Medicine Research Center

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-115610223-C-T is Benign according to our data. Variant chrX-115610223-C-T is described in ClinVar as Benign. ClinVar VariationId is 516327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLS3	NM_005032.7	MANE Select	c.-8-20C>T		intron	N/A	NP_005023.2
	PLS3	NM_001136025.5		c.-8-20C>T		intron	N/A	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.-8-20C>T		intron	N/A	NP_001427720.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLS3	ENST00000355899.8	TSL:1 MANE Select	c.-8-20C>T		intron	N/A	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.-8-20C>T		intron	N/A	ENSP00000445339.2	P13797-1
	PLS3	ENST00000489283.5	TSL:1	n.-8-20C>T		intron	N/A	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 3517 AN: 111143 Hom.: 134 Cov.: 23

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.00948 AC: 1328 AN: 140045 AF XY: 0.00472

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00573

GnomAD4 exome AF: 0.00340 AC: 2770 AN: 815820 Hom.: 97 Cov.: 12 AF XY: 0.00292 AC XY: 641 AN XY: 219762

African (AFR) AF: 0.118 AC: 2294 AN: 19455

American (AMR) AF: 0.00630 AC: 155 AN: 24605

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16001

East Asian (EAS) AF: 0.00 AC: 0 AN: 27313

South Asian (SAS) AF: 0.000288 AC: 11 AN: 38169

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39096

Middle Eastern (MID) AF: 0.00410 AC: 14 AN: 3413

European-Non Finnish (NFE) AF: 0.0000981 AC: 60 AN: 611896

Other (OTH) AF: 0.00658 AC: 236 AN: 35872

GnomAD4 genome AF: 0.0317 AC: 3522 AN: 111194 Hom.: 134 Cov.: 23 AF XY: 0.0289 AC XY: 966 AN XY: 33480

African (AFR) AF: 0.109 AC: 3344 AN: 30663

American (AMR) AF: 0.0129 AC: 134 AN: 10389

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.000374 AC: 1 AN: 2671

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5836

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 52992

Other (OTH) AF: 0.0231 AC: 35 AN: 1516

Alfa AF: 0.0159 Hom.: 77

Bravo AF: 0.0370

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.079
DANN	Benign	0.20
PhyloP100		-1.3
PromoterAI		-0.0052	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs114186394; hg19: chrX-114844535;