4-185514691-C-G

Variant names:

• chr4-185514691-C-G
• rs28447263
• NM_014476.6:c.331-354G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014476.6(PDLIM3):​c.331-354G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PDLIM3 NM_014476.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.563
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.331-354G>C		intron	N/A	NP_055291.2	Q53GG5-1
	PDLIM3	NM_001114107.5		c.518+12G>C		intron	N/A	NP_001107579.1	Q53GG5-2
	PDLIM3	NM_001257962.2		c.331-354G>C		intron	N/A	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.331-354G>C		intron	N/A	ENSP00000284767.8	Q53GG5-1
	PDLIM3	ENST00000284771.7	TSL:1	c.518+12G>C		intron	N/A	ENSP00000284771.6	Q53GG5-2
	PDLIM3	ENST00000284770.10	TSL:1	c.94-354G>C		intron	N/A	ENSP00000284770.5	A0A2U3TZH4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398302 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689570

African (AFR) AF: 0.00 AC: 0 AN: 31562

American (AMR) AF: 0.0000562 AC: 2 AN: 35618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25084

East Asian (EAS) AF: 0.00 AC: 0 AN: 35714

South Asian (SAS) AF: 0.00 AC: 0 AN: 79058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078086

Other (OTH) AF: 0.00 AC: 0 AN: 58074

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.28
DANN	Benign	0.54
PhyloP100		-0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28447263; hg19: chr4-186435845;