rs11944325

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014476.6(PDLIM3):c.379G>A(p.Val127Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,614,126 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V127L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 185 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 153 hom. )

Consequence

PDLIM3
NM_014476.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.82

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PDLIM3 links:

ENSG00000249679 (HGNC:):

ENSG00000249679 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015482306).

BP6

Variant 4-185514289-C-T is Benign according to our data. Variant chr4-185514289-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 31838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDLIM3	NM_014476.6 link	c.379G>A	p.Val127Met	missense_variant	Exon 4 of 8	ENST00000284767.12	NP_055291.2	Q53GG5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDLIM3	ENST00000284767.12 link	c.379G>A	p.Val127Met	missense_variant	Exon 4 of 8	5	NM_014476.6	ENSP00000284767.8		Q53GG5-1

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4116

AN:

152120

Hom.:

183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0931

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.00725

AC:

1824

AN:

251468

AF XY:

0.00515

show subpopulations

Gnomad AFR exome

AF:

0.0975

Gnomad AMR exome

AF:

0.00465

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000475

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00279

AC:

4079

AN:

1461888

Hom.:

153

Cov.:

AF XY:

0.00235

AC XY:

1711

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0919

AC:

3077

AN:

33480

American (AMR)

AF:

0.00563

AC:

252

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000283

AC:

315

AN:

1112006

Other (OTH)

AF:

0.00649

AC:

392

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

257

515

772

1030

1287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0271

AC:

4123

AN:

152238

Hom.:

185

Cov.:

AF XY:

0.0258

AC XY:

1921

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0930

AC:

3861

AN:

41516

American (AMR)

AF:

0.0109

AC:

166

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

68018

Other (OTH)

AF:

0.0260

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

184

368

551

735

919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.0320

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0992

AC:

437

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00911

AC:

1106

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

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:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val127Met in exon 4 of PDLIM3: This variant is not expected to have clinical s ignificance because it has been identified in 9.9% (437/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11944325). -

Aug 05, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

Apr 20, 2012

Leiden Muscular Dystrophy (PDLIM3)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 05, 2012

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.12

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.094

T;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.74

T;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.2

PhyloP100

1.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.0

N;N;.

REVEL

Benign

0.037

Sift

Benign

0.032

D;T;.

Sift4G

Benign

0.084

T;.;.

Polyphen

0.51

P;.;.

Vest4

0.18

MVP

0.61

MPC

0.32

ClinPred

0.016

GERP RS

3.5

Varity_R

0.077

gMVP

0.30

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs11944325

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over