rs112661328

chr4-185525103-G-Achr4-185525103-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_014476.6(PDLIM3):c.162C>T(p.Gly54=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,614,126 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (7 hom., cov: 33)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: PDLIM3 NM_014476.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.74

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-185525103-G-A is Benign according to our data. Variant chr4-185525103-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-185525103-G-A is described in Lovd as [Benign]. Variant chr4-185525103-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDLIM3	NM_014476.6	c.162C>T	p.Gly54=	synonymous_variant	2/8	ENST00000284767.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDLIM3	ENST00000284767.12	c.162C>T	p.Gly54=	synonymous_variant	2/8	5	NM_014476.6	A1

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1076 AN: 152204 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00799 AC: 2008 AN: 251356 Hom.: 18 AF XY: 0.00783 AC XY: 1064 AN XY: 135846

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.0102 AC: 14971 AN: 1461804 Hom.: 99 Cov.: 31 AF XY: 0.00986 AC XY: 7167 AN XY: 727212

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00505

Gnomad4 ASJ exome AF: 0.00800

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.00315

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00853

GnomAD4 genome AF: 0.00707 AC: 1077 AN: 152322 Hom.: 7 Cov.: 33 AF XY: 0.00709 AC XY: 528 AN XY: 74488

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00901 Hom.: 1

Bravo AF: 0.00667

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00911

EpiControl AF: 0.00954

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Gly54Gly in exon 2 of PDLIM3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1.0% (85/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs112661328). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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	-	- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	11
Dann	Benign	0.85

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

Other links and lift over

dbSNP: rs112661328; hg19: chr4-186446257;