chr4-185506581-G-A

Variant names:

• chr4-185506581-G-A
• rs62347360
• NM_014476.6:c.734C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (40 hom., cov: 32)
  • Exomes 𝑓: 0.024 (547 hom.)
• Consequence: PDLIM3 NM_014476.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.77
• Publications: 15 publications found

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

ENSG00000249679 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 31839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2721 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014476.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	NM_014476.6	MANE Select	c.734C>T	p.Thr245Ile	missense	Exon 6 of 8	NP_055291.2
	PDLIM3	NM_001114107.5		c.590C>T	p.Thr197Ile	missense	Exon 5 of 7	NP_001107579.1
	PDLIM3	NM_001257962.2		c.470C>T	p.Thr157Ile	missense	Exon 5 of 7	NP_001244891.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	ENST00000284767.12	TSL:5 MANE Select	c.734C>T	p.Thr245Ile	missense	Exon 6 of 8	ENSP00000284767.8
	PDLIM3	ENST00000284771.7	TSL:1	c.590C>T	p.Thr197Ile	missense	Exon 5 of 7	ENSP00000284771.6
	PDLIM3	ENST00000284770.10	TSL:1	c.233C>T	p.Thr78Ile	missense	Exon 3 of 5	ENSP00000284770.5

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2722 AN: 152194 Hom.: 40 Cov.: 32

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

GnomAD2 exomes AF: 0.0174 AC: 4364 AN: 250226 AF XY: 0.0175

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 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.: 32 AF XY: 0.0233 AC XY: 16930 AN XY: 726682

African (AFR) AF: 0.00382 AC: 128 AN: 33480

American (AMR) AF: 0.00604 AC: 270 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00388 AC: 335 AN: 86258

European-Finnish (FIN) AF: 0.0474 AC: 2477 AN: 52214

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0276 AC: 30643 AN: 1111978

Other (OTH) AF: 0.0179 AC: 1081 AN: 60384

GnomAD4 genome AF: 0.0179 AC: 2721 AN: 152312 Hom.: 40 Cov.: 32 AF XY: 0.0183 AC XY: 1364 AN XY: 74472

African (AFR) AF: 0.00469 AC: 195 AN: 41580

American (AMR) AF: 0.0110 AC: 168 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.0513 AC: 544 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0255 AC: 1735 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0215 Hom.: 149

Bravo AF: 0.0141

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0210 AC: 181

ExAC AF: 0.0172 AC: 2086

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0216

EpiControl AF: 0.0215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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.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).

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 29, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 09, 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.

not provided Benign:2 Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 20, 2012

Leiden Muscular Dystrophy (PDLIM3)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Jan 17, 2013

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.071
Sift	Benign	0.049	D
Sift4G	Uncertain	0.054	T
Polyphen		0.075	B
Vest4		0.17
MPC		0.19
ClinPred		0.0094	T
GERP RS		5.1
Varity_R		0.081
gMVP		0.19
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62347360; hg19: chr4-186427735; COSMIC: COSV99034481; COSMIC: COSV99034481;