rs11944325

chr4-185514289-C-T

Variant summary

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

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.82

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]

ACMG classification

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	UniProt
PDLIM3	NM_014476.6	c.379G>A	p.Val127Met	missense_variant	4/8	ENST00000284767.12

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4116 AN: 152120 Hom.: 183 Cov.: 32

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.: 75 AF XY: 0.00515 AC XY: 700 AN XY: 135904

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.: 33 AF XY: 0.00235 AC XY: 1711 AN XY: 727248

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.: 32 AF XY: 0.0258 AC XY: 1921 AN XY: 74450

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.: 51

Bravo AF: 0.0320

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0992 AC: 437

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00911 AC: 1106

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, 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). -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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 -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (PDLIM3)

Apr 20, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.094	T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	N;N;.
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	T
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

Other links and lift over

dbSNP: rs11944325; hg19: chr4-186435443; COSMIC: COSV52981445; COSMIC: COSV52981445;