rs7690296

Positions:

• chr4-94640308-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (11293 hom., cov: 32)
  • Exomes 𝑓: 0.43 (136396 hom.)
• Consequence: PDLIM5 NM_006457.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PDLIM5	NM_006457.5	c.1141A>G	p.Thr381Ala	missense_variant	9/13	ENST00000317968.9	NP_006448.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDLIM5	ENST00000317968.9	c.1141A>G	p.Thr381Ala	missense_variant	9/13	1	NM_006457.5	ENSP00000321746	P3

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55796 AN: 151892 Hom.: 11291 Cov.: 32

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

GnomAD3 exomes AF: 0.439 AC: 110030 AN: 250360 Hom.: 25350 AF XY: 0.453 AC XY: 61284 AN XY: 135306

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 SAS exome AF: 0.613

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.: 30 AF XY: 0.435 AC XY: 315009 AN XY: 724146

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.418

Gnomad4 ASJ exome AF: 0.502

Gnomad4 EAS exome AF: 0.402

Gnomad4 SAS exome AF: 0.610

Gnomad4 FIN exome AF: 0.490

Gnomad4 NFE exome AF: 0.416

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.367 AC: 55810 AN: 152008 Hom.: 11293 Cov.: 32 AF XY: 0.375 AC XY: 27888 AN XY: 74294

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.504

Gnomad4 EAS AF: 0.405

Gnomad4 SAS AF: 0.620

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.380

Alfa AF: 0.417 Hom.: 34985

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	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0030
DANN	Benign	0.24
DEOGEN2	Benign	0.0079	T;.;T;.;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.10	T;T;T;T;T;.
MetaRNN	Benign	0.000013	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;.;L;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.26	T
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	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.26

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: rs7690296; hg19: chr4-95561459; COSMIC: COSV58745700;