rs34943562

Variant names:

• chr4-185506637-C-T
• rs34943562
• NM_014476.6:c.678G>A
• PDLIM3 p.Ser226Ser

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014476.6(PDLIM3):​c.678G>A​(p.Ser226Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,605,846 control chromosomes in the GnomAD database, including 408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (224 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (184 hom.)
• Consequence: PDLIM3 NM_014476.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.77
• Publications: 2 publications found

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

ENSG00000249679 (HGNC:58917):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-185506637-C-T is Benign according to our data. Variant chr4-185506637-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.097 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	NM_014476.6	MANE Select	c.678G>A	p.Ser226Ser	synonymous	Exon 6 of 8	NP_055291.2	Q53GG5-1
	PDLIM3	NM_001114107.5		c.534G>A	p.Ser178Ser	synonymous	Exon 5 of 7	NP_001107579.1	Q53GG5-2
	PDLIM3	NM_001257962.2		c.414G>A	p.Ser138Ser	synonymous	Exon 5 of 7	NP_001244891.1	A0A087WYF8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	ENST00000284767.12	TSL:5 MANE Select	c.678G>A	p.Ser226Ser	synonymous	Exon 6 of 8	ENSP00000284767.8	Q53GG5-1
	PDLIM3	ENST00000284771.7	TSL:1	c.534G>A	p.Ser178Ser	synonymous	Exon 5 of 7	ENSP00000284771.6	Q53GG5-2
	PDLIM3	ENST00000284770.10	TSL:1	c.177G>A	p.Ser59Ser	synonymous	Exon 3 of 5	ENSP00000284770.5	A0A2U3TZH4

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4394 AN: 152062 Hom.: 221 Cov.: 32

Gnomad AFR AF: 0.0996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0264

GnomAD2 exomes AF: 0.00793 AC: 1939 AN: 244422 AF XY: 0.00561

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00495

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00302 AC: 4392 AN: 1453666 Hom.: 184 Cov.: 32 AF XY: 0.00254 AC XY: 1840 AN XY: 723364

African (AFR) AF: 0.0998 AC: 3342 AN: 33476

American (AMR) AF: 0.00593 AC: 265 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45356

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5766

European-Non Finnish (NFE) AF: 0.000283 AC: 315 AN: 1111914

Other (OTH) AF: 0.00706 AC: 426 AN: 60350

GnomAD4 genome AF: 0.0290 AC: 4406 AN: 152180 Hom.: 224 Cov.: 32 AF XY: 0.0276 AC XY: 2051 AN XY: 74392

African (AFR) AF: 0.0996 AC: 4133 AN: 41510

American (AMR) AF: 0.0117 AC: 179 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68008

Other (OTH) AF: 0.0261 AC: 55 AN: 2106

Alfa AF: 0.0143 Hom.: 56

Bravo AF: 0.0340

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.20
DANN	Benign	0.50
PhyloP100		-2.8
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34943562;

hg19: chr4-186427791;