rs200354645

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7

The NM_014476.6(PDLIM3):c.246G>A(p.Arg82Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,586,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

PDLIM3
NM_014476.6 splice_region, synonymous

Scores

Splicing: ADA: 0.006168

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.05

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15728128).

BP6

Variant 4-185523446-C-T is Benign according to our data. Variant chr4-185523446-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380756.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr4-185523446-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.05 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDLIM3	NM_014476.6 link	c.246G>A	p.Arg82Arg	splice_region_variant, synonymous_variant	Exon 3 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.246G>A	p.Arg82Arg	splice_region_variant, synonymous_variant	Exon 3 of 8	5	NM_014476.6	ENSP00000284767.8		Q53GG5-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000261

AC:

AN:

248824

AF XY:

0.000312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000381

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000167

AC:

239

AN:

1434516

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

129

AN XY:

715190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

32948

Gnomad4 AMR exome

AF:

0.000202

AC:

AN:

44566

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25918

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39518

Gnomad4 SAS exome

AF:

0.000235

AC:

AN:

85232

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53138

Gnomad4 NFE exome

AF:

0.000168

AC:

183

AN:

1087974

Gnomad4 Remaining exome

AF:

0.000286

AC:

AN:

59510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000196

AC:

0.000196078

AN:

0.000196078

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000207297

AN:

0.000207297

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000206

AC:

0.00020581

AN:

0.00020581

Gnomad4 OTH

AF:

0.000473

AC:

0.00047259

AN:

0.00047259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000235

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000654

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 07, 2017

GeneDx

Significance:Likely 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. -

Oct 14, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy

Uncertain:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 82 of the PDLIM3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PDLIM3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200354645, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PDLIM3-related conditions. ClinVar contains an entry for this variant (Variation ID: 380756). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.062

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.45

M_CAP

Benign

0.073

MetaRNN

Benign

0.16

Sift4G

Uncertain

0.041

Vest4

0.43

MVP

0.43

GERP RS

3.5

Mutation Taster

=47/53

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0062

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.030

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