4-185502105-GT-G

Variant names:

• chr4-185502105-GT-G
• rs199939796
• NM_014476.6:c.*188delA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014476.6(PDLIM3):​c.*188delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000002 in 500,022 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: PDLIM3 NM_014476.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.*188delA		3_prime_UTR	Exon 8 of 8	NP_055291.2	Q53GG5-1
	PDLIM3	NM_001114107.5		c.*188delA		3_prime_UTR	Exon 7 of 7	NP_001107579.1	Q53GG5-2
	PDLIM3	NM_001257962.2		c.*188delA		3_prime_UTR	Exon 7 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.*188delA		3_prime_UTR	Exon 8 of 8	ENSP00000284767.8	Q53GG5-1
	PDLIM3	ENST00000284771.7	TSL:1	c.*188delA		3_prime_UTR	Exon 7 of 7	ENSP00000284771.6	Q53GG5-2
	PDLIM3	ENST00000284770.10	TSL:1	c.*188delA		3_prime_UTR	Exon 5 of 5	ENSP00000284770.5	A0A2U3TZH4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000200 AC: 1 AN: 500022 Hom.: 0 Cov.: 6 AF XY: 0.00000378 AC XY: 1 AN XY: 264616

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 13576

American (AMR) AF: 0.00 AC: 0 AN: 24842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15880

East Asian (EAS) AF: 0.00 AC: 0 AN: 31038

South Asian (SAS) AF: 0.00 AC: 0 AN: 50440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2122

European-Non Finnish (NFE) AF: 0.00000334 AC: 1 AN: 299074

Other (OTH) AF: 0.00 AC: 0 AN: 27682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11

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: rs199939796; hg19: chr4-186423259; COSMIC: COSV52981673; COSMIC: COSV52981673;