3-142684133-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001145319.2(PLS1):c.707T>C(p.Val236Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00486 in 1,614,058 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (18 hom.)
• Consequence: PLS1 NM_001145319.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.78

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014731824).
• BP6: Variant 3-142684133-T-C is Benign according to our data. Variant chr3-142684133-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2571191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 530 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLS1	NM_001145319.2	c.707T>C	p.Val236Ala	missense_variant	7/16	ENST00000457734.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLS1	ENST00000457734.7	c.707T>C	p.Val236Ala	missense_variant	7/16	2	NM_001145319.2	P1
	ENST00000690164.1	n.119-26927A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00570

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00309 AC: 776 AN: 251224 Hom.: 2 AF XY: 0.00303 AC XY: 412 AN XY: 135780

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00455

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00500 AC: 7315 AN: 1461782 Hom.: 18 Cov.: 32 AF XY: 0.00484 AC XY: 3519 AN XY: 727184

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.00658

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00584

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00301 AC XY: 224 AN XY: 74460

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00570

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00469 Hom.: 3

Bravo AF: 0.00345

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00277 AC: 336

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00403

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PLS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

PLS1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;D;D
Eigen	Benign	-0.041
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.26	N;.;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.0040	B;.;B;B
Vest4		0.26
MVP		0.93
MPC		0.24
ClinPred		0.056	T
GERP RS		5.0
Varity_R		0.69
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148154571; hg19: chr3-142402975;