rs142951316

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014476.6(PDLIM3):c.169A>G(p.Thr57Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000431 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T57T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

PDLIM3
NM_014476.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 3.87

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PDLIM3 links:

ENSG00000249679 (HGNC:58917):

ENSG00000249679 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041879654).

BP6

Variant 4-185525096-T-C is Benign according to our data. Variant chr4-185525096-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229140.

BS2

High AC in GnomAd4 at 46 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDLIM3	NM_014476.6	MANE Select	c.169A>G	p.Thr57Ala	missense	Exon 2 of 8	NP_055291.2	Q53GG5-1
PDLIM3	NM_001114107.5		c.169A>G	p.Thr57Ala	missense	Exon 2 of 7	NP_001107579.1	Q53GG5-2
PDLIM3	NM_001257962.2		c.169A>G	p.Thr57Ala	missense	Exon 2 of 7	NP_001244891.1	A0A087WYF8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDLIM3	ENST00000284767.12	TSL:5 MANE Select	c.169A>G	p.Thr57Ala	missense	Exon 2 of 8	ENSP00000284767.8	Q53GG5-1
PDLIM3	ENST00000284771.7	TSL:1	c.169A>G	p.Thr57Ala	missense	Exon 2 of 7	ENSP00000284771.6	Q53GG5-2
PDLIM3	ENST00000284770.10	TSL:1	c.93+10246A>G		intron	N/A	ENSP00000284770.5	A0A2U3TZH4

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000330

AC:

AN:

251376

AF XY:

0.000317

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000445

AC:

650

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

299

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000872

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000501

AC:

557

AN:

1111976

Other (OTH)

AF:

0.000795

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000302

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41574

American (AMR)

AF:

0.000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000445

Hom.:

Bravo

AF:

0.000419

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

0.016

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

M_CAP

Benign

0.014

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

3.9

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.090

Sift

Benign

0.11

Sift4G

Benign

0.18

Polyphen

0.17

Vest4

0.34

MVP

0.70

ClinPred

0.050

GERP RS

5.4

Varity_R

0.20

gMVP

0.53

Mutation Taster

=33/67

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over