NM_014476.6:c.715G>A

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.715G>A(p.Asp239Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,611,612 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D239G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

PDLIM3
NM_014476.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.21

Publications

4 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=0.004471153).

BP6

Variant 4-185506600-C-T is Benign according to our data. Variant chr4-185506600-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201953.

BS2

High AC in GnomAd4 at 63 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.715G>A	p.Asp239Asn	missense	Exon 6 of 8	NP_055291.2	Q53GG5-1
PDLIM3	NM_001114107.5		c.571G>A	p.Asp191Asn	missense	Exon 5 of 7	NP_001107579.1	Q53GG5-2
PDLIM3	NM_001257962.2		c.451G>A	p.Asp151Asn	missense	Exon 5 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.715G>A	p.Asp239Asn	missense	Exon 6 of 8	ENSP00000284767.8	Q53GG5-1
PDLIM3	ENST00000284771.7	TSL:1	c.571G>A	p.Asp191Asn	missense	Exon 5 of 7	ENSP00000284771.6	Q53GG5-2
PDLIM3	ENST00000284770.10	TSL:1	c.214G>A	p.Asp72Asn	missense	Exon 3 of 5	ENSP00000284770.5	A0A2U3TZH4

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000731

AC:

182

AN:

249114

AF XY:

0.000660

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.000103

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000332

AC:

484

AN:

1459462

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

245

AN XY:

726114

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

340

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000392

AC:

AN:

51056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1111970

Other (OTH)

AF:

0.000977

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000414

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41438

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68016

Other (OTH)

AF:

0.00144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000653

Hom.:

Bravo

AF:

0.000468

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000478

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

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 (1)

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy (1)

Familial cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.015

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

1.2

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.055

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

0.0010

Vest4

0.14

MVP

0.62

MPC

0.15

ClinPred

0.021

GERP RS

3.3

Varity_R

0.16

gMVP

0.37

Mutation Taster

=100/0

polymorphism

(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