rs11944325

Positions:

chr4-185514289-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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

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:

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=0.0015482306).

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. Variant chr4-185514289-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PDLIM3	NM_014476.6 linkuse as main transcript	c.379G>A	p.Val127Met	missense_variant	4/8	ENST00000284767.12	NP_055291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDLIM3	ENST00000284767.12 linkuse as main transcript	c.379G>A	p.Val127Met	missense_variant	4/8	5	NM_014476.6	ENSP00000284767	A1	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

GnomAD3 exomes

AF:

0.00725

AC:

1824

AN:

251468

Hom.:

AF XY:

0.00515

AC XY:

700

AN XY:

135904

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 SAS exome

AF:

0.0000980

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

Gnomad4 AFR exome

AF:

0.0919

Gnomad4 AMR exome

AF:

0.00563

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000283

Gnomad4 OTH exome

AF:

0.00649

GnomAD4 genome

AF:

0.0271

AC:

4123

AN:

152238

Hom.:

185

Cov.:

AF XY:

0.0258

AC XY:

1921

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0930

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0120

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -

not provided

Benign:1Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (PDLIM3)	Apr 20, 2012	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2012

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

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

MutationTaster

Benign

1.0

D;D;N

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

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

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