4-185514691-C-T

Variant names:

• chr4-185514691-C-T
• rs28447263
• ENST00000514142.5:n.3027G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000514142.5(PDLIM3):​n.3027G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,550,504 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (143 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (115 hom.)
• Consequence: PDLIM3 ENST00000514142.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.563
• Publications: 1 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:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-185514691-C-T is Benign according to our data. Variant chr4-185514691-C-T is described in ClinVar as Benign. ClinVar VariationId is 227012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000514142.5. 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.331-354G>A		intron	N/A	NP_055291.2
	PDLIM3	NM_001114107.5		c.518+12G>A		intron	N/A	NP_001107579.1
	PDLIM3	NM_001257962.2		c.331-354G>A		intron	N/A	NP_001244891.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	ENST00000514142.5	TSL:1	n.3027G>A		non_coding_transcript_exon	Exon 1 of 4
	PDLIM3	ENST00000284767.12	TSL:5 MANE Select	c.331-354G>A		intron	N/A	ENSP00000284767.8
	PDLIM3	ENST00000284771.7	TSL:1	c.518+12G>A		intron	N/A	ENSP00000284771.6

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3569 AN: 152106 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00492 AC: 774 AN: 157160 AF XY: 0.00402

Gnomad AFR exome AF: 0.0791

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000442

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.00248 AC: 3463 AN: 1398280 Hom.: 115 Cov.: 30 AF XY: 0.00216 AC XY: 1491 AN XY: 689560

African (AFR) AF: 0.0840 AC: 2649 AN: 31542

American (AMR) AF: 0.00432 AC: 154 AN: 35618

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

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35714

South Asian (SAS) AF: 0.000253 AC: 20 AN: 79058

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

Middle Eastern (MID) AF: 0.00492 AC: 28 AN: 5690

European-Non Finnish (NFE) AF: 0.000224 AC: 241 AN: 1078084

Other (OTH) AF: 0.00637 AC: 370 AN: 58074

GnomAD4 genome AF: 0.0235 AC: 3576 AN: 152224 Hom.: 143 Cov.: 32 AF XY: 0.0224 AC XY: 1669 AN XY: 74430

African (AFR) AF: 0.0821 AC: 3407 AN: 41522

American (AMR) AF: 0.00686 AC: 105 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68006

Other (OTH) AF: 0.00995 AC: 21 AN: 2110

Alfa AF: 0.00386 Hom.: 4

Bravo AF: 0.0258

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.35
DANN	Benign	0.71
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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;