3-142676175-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001145319.2(PLS1):c.383T>C(p.Phe128Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLS1 NM_001145319.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.02

Genes affected

PLS1 (HGNC:9090): (plastin 1) 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. The protein encoded by this gene is a third distinct plastin isoform, which is specifically expressed at high levels in the small intestine. Alternatively spliced transcript variants varying in the 5' UTR, but encoding the same protein, have been found for this gene. A pseudogene of this gene is found on chromosome 11.[provided by RefSeq, Feb 2010]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 3-142676175-T-C is Pathogenic according to our data. Variant chr3-142676175-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633603.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLS1	NM_001145319.2	c.383T>C	p.Phe128Ser	missense_variant	5/16	ENST00000457734.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLS1	ENST00000457734.7	c.383T>C	p.Phe128Ser	missense_variant	5/16	2	NM_001145319.2	P1
	ENST00000690164.1	n.119-18969A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Bilateral sensorineural hearing impairment;C5779548:Autosomal dominant nonsyndromic hearing loss Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory of Molecular Genetics, Montpellier University Hospital

May 29, 2019

The p.(Phe128Ser) variant in PLS1 has been reported in 3 individuals of the same family (3 generations) presenting with the phenotype. The variant is absent from large population studies and predicted to possibly alter the structure of the protein. It is then considered as likely pathogenic. -

Hearing loss, autosomal dominant 76 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.5	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.98
MutPred		0.73		Gain of disorder (P = 0.003);.;Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.93
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1577876794; hg19: chr3-142395017;