NM_014476.6:c.847G>A

Variant names:

• chr4-185504533-C-T
• rs779988849
• NM_014476.6:c.847G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014476.6(PDLIM3):​c.847G>A​(p.Gly283Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G283G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PDLIM3 NM_014476.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0490
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05456704).
• BS2: High AC in GnomAdExome4 at 33 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	NM_014476.6	MANE Select	c.847G>A	p.Gly283Ser	missense	Exon 7 of 8	NP_055291.2	Q53GG5-1
	PDLIM3	NM_001114107.5		c.703G>A	p.Gly235Ser	missense	Exon 6 of 7	NP_001107579.1	Q53GG5-2
	PDLIM3	NM_001257962.2		c.583G>A	p.Gly195Ser	missense	Exon 6 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.847G>A	p.Gly283Ser	missense	Exon 7 of 8	ENSP00000284767.8	Q53GG5-1
	PDLIM3	ENST00000284771.7	TSL:1	c.703G>A	p.Gly235Ser	missense	Exon 6 of 7	ENSP00000284771.6	Q53GG5-2
	PDLIM3	ENST00000284770.10	TSL:1	c.346G>A	p.Gly116Ser	missense	Exon 4 of 5	ENSP00000284770.5	A0A2U3TZH4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251408 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1112004

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000762 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.6
DANN	Benign	0.88
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.12	N
PhyloP100		0.049
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.077
Sift	Benign	0.51	T
Sift4G	Benign	0.50	T
Polyphen		0.0010	B
Vest4		0.29
MVP		0.35
MPC		0.16
ClinPred		0.097	T
GERP RS		3.8
Varity_R		0.083
gMVP		0.22
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs779988849; hg19: chr4-186425687; COSMIC: COSV52979024; COSMIC: COSV52979024;