NM_005032.7:c.74-236A>G

Variant names:

• chrX-115622010-A-G
• rs114536525
• NM_005032.7:c.74-236A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005032.7(PLS3):​c.74-236A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 317,733 control chromosomes in the GnomAD database, including 238 homozygotes. There are 1,379 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (203 hom., 1129 hem., cov: 23)
  • Exomes 𝑓: 0.0050 (35 hom. 250 hem.)
• Consequence: PLS3 NM_005032.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0890
• 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, Ambry Genetics, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-115622010-A-G is Benign according to our data. Variant chrX-115622010-A-G is described in ClinVar as Benign. ClinVar VariationId is 1259784.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 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.74-236A>G		intron	N/A	NP_005023.2
	PLS3	NM_001136025.5		c.74-236A>G		intron	N/A	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.74-236A>G		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.74-236A>G		intron	N/A	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.74-236A>G		intron	N/A	ENSP00000445339.2	P13797-1
	PLS3	ENST00000489283.5	TSL:1	n.*327-236A>G		intron	N/A	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes AF: 0.0377 AC: 4212 AN: 111754 Hom.: 203 Cov.: 23

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00406

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.0260

GnomAD4 exome AF: 0.00504 AC: 1037 AN: 205923 Hom.: 35 Cov.: 0 AF XY: 0.00487 AC XY: 250 AN XY: 51367

African (AFR) AF: 0.131 AC: 720 AN: 5491

American (AMR) AF: 0.00864 AC: 52 AN: 6020

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 10 AN: 6812

East Asian (EAS) AF: 0.00 AC: 0 AN: 14055

South Asian (SAS) AF: 0.00512 AC: 53 AN: 10356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16126

Middle Eastern (MID) AF: 0.00416 AC: 4 AN: 961

European-Non Finnish (NFE) AF: 0.000309 AC: 41 AN: 132585

Other (OTH) AF: 0.0116 AC: 157 AN: 13517

GnomAD4 genome AF: 0.0378 AC: 4228 AN: 111810 Hom.: 203 Cov.: 23 AF XY: 0.0332 AC XY: 1129 AN XY: 33994

African (AFR) AF: 0.130 AC: 3999 AN: 30736

American (AMR) AF: 0.0154 AC: 161 AN: 10472

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00407 AC: 11 AN: 2703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6036

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

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53211

Other (OTH) AF: 0.0276 AC: 42 AN: 1519

Alfa AF: 0.0296 Hom.: 94

Bravo AF: 0.0440

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.41
DANN	Benign	0.63
PhyloP100		-0.089
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: rs114536525; hg19: chrX-114856322;