4-185514281-C-T

Variant names:

• chr4-185514281-C-T
• rs138670107
• NM_014476.6:c.387G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_014476.6(PDLIM3):​c.387G>A​(p.Pro129Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,168 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (8 hom.)
• Consequence: PDLIM3 NM_014476.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.22
• Publications: 3 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 4-185514281-C-T is Benign according to our data. Variant chr4-185514281-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.22 with no splicing effect.
• BS2: High AC in GnomAd4 at 163 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	NM_014476.6	MANE Select	c.387G>A	p.Pro129Pro	synonymous	Exon 4 of 8	NP_055291.2
	PDLIM3	NM_001257962.2		c.387G>A	p.Pro129Pro	synonymous	Exon 4 of 7	NP_001244891.1
	PDLIM3	NM_001257963.2		c.150G>A	p.Pro50Pro	synonymous	Exon 2 of 5	NP_001244892.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	ENST00000284767.12	TSL:5 MANE Select	c.387G>A	p.Pro129Pro	synonymous	Exon 4 of 8	ENSP00000284767.8
	PDLIM3	ENST00000284770.10	TSL:1	c.150G>A	p.Pro50Pro	synonymous	Exon 2 of 5	ENSP00000284770.5
	PDLIM3	ENST00000284771.7	TSL:1	c.518+422G>A		intron	N/A	ENSP00000284771.6

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00146 AC: 366 AN: 251460 AF XY: 0.00149

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00134 AC: 1965 AN: 1461890 Hom.: 8 Cov.: 33 AF XY: 0.00138 AC XY: 1002 AN XY: 727248

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86256

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00152 AC: 1694 AN: 1112010

Other (OTH) AF: 0.000745 AC: 45 AN: 60396

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74468

African (AFR) AF: 0.000144 AC: 6 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000990

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.3
DANN	Benign	0.81
PhyloP100		2.2
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs138670107; hg19: chr4-186435435;