Genetic Variant NM_006457.5:c.1141A>G (chr4-94640308-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006457.5(PDLIM5):c.1141A>G(p.Thr381Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,606,886 control chromosomes in the GnomAD database, including 147,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.37 ( 11293 hom., cov: 32)

Exomes 𝑓: 0.43 ( 136396 hom. )

Consequence

PDLIM5
NM_006457.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.44

Publications

51 publications found

Variant links:

Genes affected

PDLIM5 (HGNC:17468): (PDZ and LIM domain 5) This gene encodes a member of a family of proteins that possess a 100-amino acid PDZ domain at the N terminus and one to three LIM domains at the C-terminus. This family member functions as a scaffold protein that tethers protein kinases to the Z-disk in striated muscles. It is thought to function in cardiomyocyte expansion and in restraining postsynaptic growth of excitatory synapses. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2012]

PDLIM5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2841005E-5).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDLIM5	NM_006457.5 link	c.1141A>G	p.Thr381Ala	missense_variant	Exon 9 of 13	ENST00000317968.9	NP_006448.5	Q96HC4-1A0A024RDE8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDLIM5	ENST00000317968.9 link	c.1141A>G	p.Thr381Ala	missense_variant	Exon 9 of 13	1	NM_006457.5	ENSP00000321746.4		Q96HC4-1

Frequencies

GnomAD3 genomes

AF:

0.367

AC:

55796

AN:

151892

Hom.:

11291

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.493

Gnomad AMR

AF:

0.391

Gnomad ASJ

AF:

0.504

Gnomad EAS

AF:

0.404

Gnomad SAS

AF:

0.623

Gnomad FIN

AF:

0.495

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.421

Gnomad OTH

AF:

0.374

GnomAD2 exomes

AF:

0.439

AC:

110030

AN:

250360

AF XY:

0.453

show subpopulations

Gnomad AFR exome

AF:

0.180

Gnomad AMR exome

AF:

0.425

Gnomad ASJ exome

AF:

0.504

Gnomad EAS exome

AF:

0.398

Gnomad FIN exome

AF:

0.495

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.453

GnomAD4 exome

AF:

0.427

AC:

621113

AN:

1454878

Hom.:

136396

Cov.:

AF XY:

0.435

AC XY:

315009

AN XY:

724146

show subpopulations

African (AFR)

AF:

0.180

AC:

6001

AN:

33358

American (AMR)

AF:

0.418

AC:

18627

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.502

AC:

13082

AN:

26054

East Asian (EAS)

AF:

0.402

AC:

15934

AN:

39640

South Asian (SAS)

AF:

0.610

AC:

52417

AN:

85950

European-Finnish (FIN)

AF:

0.490

AC:

26154

AN:

53388

Middle Eastern (MID)

AF:

0.498

AC:

2865

AN:

5758

European-Non Finnish (NFE)

AF:

0.416

AC:

460226

AN:

1106036

Other (OTH)

AF:

0.429

AC:

25807

AN:

60118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15438

30877

46315

61754

77192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14068

28136

42204

56272

70340

<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:

0.367

AC:

55810

AN:

152008

Hom.:

11293

Cov.:

AF XY:

0.375

AC XY:

27888

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.188

AC:

7791

AN:

41474

American (AMR)

AF:

0.391

AC:

5961

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.504

AC:

1748

AN:

3470

East Asian (EAS)

AF:

0.405

AC:

2088

AN:

5156

South Asian (SAS)

AF:

0.620

AC:

2988

AN:

4818

European-Finnish (FIN)

AF:

0.495

AC:

5225

AN:

10564

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.421

AC:

28599

AN:

67950

Other (OTH)

AF:

0.380

AC:

803

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1716

3431

5147

6862

8578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

552

1104

1656

2208

2760

<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:

0.408

Hom.:

49181

Bravo

AF:

0.350

TwinsUK

AF:

0.418

AC:

1550

ALSPAC

AF:

0.412

AC:

1588

ESP6500AA

AF:

0.186

AC:

821

ESP6500EA

AF:

0.422

AC:

3630

ExAC

AF:

0.435

AC:

52807

Asia WGS

AF:

0.503

AC:

1745

AN:

3478

EpiCase

AF:

0.428

EpiControl

AF:

0.438

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.0030

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.0079

T;.;T;.;.;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.10

T;T;T;T;T;.

MetaRNN

Benign

0.000013

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

.;.;L;.;.;.

PhyloP100

-1.4

PrimateAI

Benign

0.26

PROVEAN

Benign

0.26

.;.;N;N;.;N

REVEL

Benign

0.023

Sift

Benign

1.0

.;.;T;T;.;T

Sift4G

Benign

0.89

T;T;T;T;T;T

Polyphen

0.0

.;.;B;.;B;.

Vest4

0.032

MPC

0.10

ClinPred

0.018

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.068

gMVP

0.26

Mutation Taster

=96/4

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over