3-142676230-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145319.2(PLS1):c.438A>G(p.Ile146Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,613,056 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (86 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (62 hom.)
• Consequence: PLS1 NM_001145319.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.945

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005818069).
• BP6: Variant 3-142676230-A-G is Benign according to our data. Variant chr3-142676230-A-G is described in ClinVar as [Benign]. Clinvar id is 1263460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLS1	NM_001145319.2	c.438A>G	p.Ile146Met	missense_variant	5/16	ENST00000457734.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLS1	ENST00000457734.7	c.438A>G	p.Ile146Met	missense_variant	5/16	2	NM_001145319.2	P1
	ENST00000690164.1	n.119-19024T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2746 AN: 152152 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00469 AC: 1179 AN: 251138 Hom.: 43 AF XY: 0.00355 AC XY: 482 AN XY: 135740

Gnomad AFR exome AF: 0.0619

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00184 AC: 2695 AN: 1460786 Hom.: 62 Cov.: 29 AF XY: 0.00165 AC XY: 1198 AN XY: 726812

Gnomad4 AFR exome AF: 0.0617

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.0181 AC: 2760 AN: 152270 Hom.: 86 Cov.: 32 AF XY: 0.0177 AC XY: 1314 AN XY: 74438

Gnomad4 AFR AF: 0.0623

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00334 Hom.: 25

Bravo AF: 0.0200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0611 AC: 269

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00568 AC: 689

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PLS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	13
Dann	Benign	0.97
DEOGEN2	Benign	0.32	T;.;T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.056	N
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L;.;L;L
MutationTaster	Benign	0.99	P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.021	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.13	B;.;B;B
Vest4		0.28
MVP		0.61
MPC		0.40
ClinPred		0.0099	T
GERP RS		-6.3
Varity_R		0.13
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs35710125; hg19: chr3-142395072;