X-115610944-C-A

Variant names:

• chrX-115610944-C-A
• rs5987754
• NM_005032.7:c.73+621C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0650
• 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 XL gene

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.73+621C>A		intron	N/A	NP_005023.2
	PLS3	NM_001136025.5		c.73+621C>A		intron	N/A	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.73+621C>A		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.73+621C>A		intron	N/A	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.73+621C>A		intron	N/A	ENSP00000445339.2	P13797-1
	PLS3	ENST00000489283.5	TSL:1	n.73+621C>A		intron	N/A	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 1665 AN: 110751 Hom.: 23 Cov.: 24

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

GnomAD2 exomes AF: 0.00452 AC: 381 AN: 84217 AF XY: 0.00266

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 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

African (AFR) AF: 0.0509 AC: 932 AN: 18325

American (AMR) AF: 0.00658 AC: 176 AN: 26745

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 35 AN: 16389

East Asian (EAS) AF: 0.00 AC: 0 AN: 25269

South Asian (SAS) AF: 0.000169 AC: 7 AN: 41526

European-Finnish (FIN) AF: 0.0000790 AC: 2 AN: 25317

Middle Eastern (MID) AF: 0.0111 AC: 38 AN: 3411

European-Non Finnish (NFE) AF: 0.00127 AC: 647 AN: 509249

Other (OTH) AF: 0.00753 AC: 248 AN: 32929

GnomAD4 genome AF: 0.0150 AC: 1667 AN: 110807 Hom.: 23 Cov.: 24 AF XY: 0.0131 AC XY: 432 AN XY: 33089

African (AFR) AF: 0.0477 AC: 1457 AN: 30544

American (AMR) AF: 0.00936 AC: 97 AN: 10367

Ashkenazi Jewish (ASJ) AF: 0.00265 AC: 7 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.000767 AC: 2 AN: 2608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5921

Middle Eastern (MID) AF: 0.0233 AC: 5 AN: 215

European-Non Finnish (NFE) AF: 0.00148 AC: 78 AN: 52797

Other (OTH) AF: 0.0141 AC: 21 AN: 1494

Alfa AF: 0.00581 Hom.: 139

Bravo AF: 0.0173

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.3
DANN	Benign	0.76
PhyloP100		0.065
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5987754; hg19: chrX-114845256;