rs62347360

Positions:

chr4-185506581-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014476.6(PDLIM3):c.734C>T(p.Thr245Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,612,954 control chromosomes in the GnomAD database, including 587 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T245T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.018 ( 40 hom., cov: 32)

Exomes 𝑓: 0.024 ( 547 hom. )

Consequence

PDLIM3
NM_014476.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.77

Variant links:

Genes affected

PDLIM3 (HGNC:20767): (PDZ and LIM domain 3) The protein encoded by this gene contains a PDZ domain and a LIM domain, indicating that it may be involved in cytoskeletal assembly. In support of this, the encoded protein has been shown to bind the spectrin-like repeats of alpha-actinin-2 and to colocalize with alpha-actinin-2 at the Z lines of skeletal muscle. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Aberrant alternative splicing of this gene may play a role in myotonic dystrophy. [provided by RefSeq, Apr 2012]

PDLIM3 links:

PDLIM3 (HGNC:):

PDLIM3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002310574).

BP6

Variant 4-185506581-G-A is Benign according to our data. Variant chr4-185506581-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 31839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-185506581-G-A is described in Lovd as [Likely_benign]. Variant chr4-185506581-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2721/152312) while in subpopulation NFE AF= 0.0255 (1735/68028). AF 95% confidence interval is 0.0245. There are 40 homozygotes in gnomad4. There are 1364 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDLIM3	NM_014476.6 linkuse as main transcript	c.734C>T	p.Thr245Ile	missense_variant	6/8	ENST00000284767.12	NP_055291.2	Q53GG5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDLIM3	ENST00000284767.12 linkuse as main transcript	c.734C>T	p.Thr245Ile	missense_variant	6/8	5	NM_014476.6	ENSP00000284767.8		Q53GG5-1

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2722

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00470

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0513

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0174

AC:

4364

AN:

250226

Hom.:

AF XY:

0.0175

AC XY:

2369

AN XY:

135310

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.00567

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00376

Gnomad FIN exome

AF:

0.0487

Gnomad NFE exome

AF:

0.0253

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.0240

AC:

35060

AN:

1460642

Hom.:

547

Cov.:

AF XY:

0.0233

AC XY:

16930

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.00382

Gnomad4 AMR exome

AF:

0.00604

Gnomad4 ASJ exome

AF:

0.00429

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00388

Gnomad4 FIN exome

AF:

0.0474

Gnomad4 NFE exome

AF:

0.0276

Gnomad4 OTH exome

AF:

0.0179

GnomAD4 genome

AF:

0.0179

AC:

2721

AN:

152312

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1364

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00469

Gnomad4 AMR

AF:

0.0110

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0513

Gnomad4 NFE

AF:

0.0255

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0219

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.0297

AC:

110

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0210

AC:

181

ExAC

AF:

0.0172

AC:

2086

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0216

EpiControl

AF:

0.0215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Thr245Ile in exon 6 of PDLIM3: This variant is not expected to have clinical s ignificance because it has been identified in 2.1% (181/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs62347360). -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (PDLIM3)	Apr 20, 2012	- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2013

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.23

T;.;.;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.92

D;D;D;D

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.8

.;.;N;.

REVEL

Benign

0.071

Sift

Benign

0.049

.;.;D;.

Sift4G

Uncertain

0.054

.;.;T;.

Polyphen

0.075

B;.;B;.

Vest4

0.17

MPC

0.19

ClinPred

0.0094

GERP RS

5.1

Varity_R

0.081

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over