chrX-115622259-C-A

Variant names:

• chrX-115622259-C-A
• rs972895977
• NM_005032.7:c.87C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005032.7(PLS3):​c.87C>A​(p.Asn29Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000923 in 1,083,945 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N29S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: PLS3 NM_005032.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.87C>A	p.Asn29Lys	missense	Exon 3 of 16	NP_005023.2
	PLS3	NM_001136025.5		c.87C>A	p.Asn29Lys	missense	Exon 3 of 16	NP_001129497.1	P13797-1
	PLS3	NM_001440791.1		c.87C>A	p.Asn29Lys	missense	Exon 4 of 17	NP_001427720.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLS3	ENST00000355899.8	TSL:1 MANE Select	c.87C>A	p.Asn29Lys	missense	Exon 3 of 16	ENSP00000348163.3	P13797-1
	PLS3	ENST00000539310.5	TSL:1	c.87C>A	p.Asn29Lys	missense	Exon 3 of 16	ENSP00000445339.2	P13797-1
	PLS3	ENST00000489283.5	TSL:1	n.*340C>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000420458.1	F2Z2Z9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083945 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 351465

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25938

American (AMR) AF: 0.00 AC: 0 AN: 33135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19108

East Asian (EAS) AF: 0.00 AC: 0 AN: 29770

South Asian (SAS) AF: 0.00 AC: 0 AN: 50371

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40469

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835464

Other (OTH) AF: 0.00 AC: 0 AN: 45589

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.087
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.014	D
Sift4G	Benign	0.95	T
Polyphen		0.49	P
Vest4		0.36
MutPred		0.56		Gain of ubiquitination at N29 (P = 0.0198)
MVP		0.70
MPC		1.4
ClinPred		0.96	D
GERP RS		1.6
Varity_R		0.44
gMVP		0.80
Mutation Taster		=57/43	polymorphism

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: rs972895977; hg19: chrX-114856571;