4-185502282-G-A

Position:

• chr4-185502282-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014476.6(PDLIM3):​c.*12C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,613,670 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (17 hom., cov: 33)
  • Exomes 𝑓: 0.012 (147 hom.)
• Consequence: PDLIM3 NM_014476.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.99

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-185502282-G-A is Benign according to our data. Variant chr4-185502282-G-A is described in ClinVar as [Benign]. Clinvar id is 138676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-185502282-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0093 (1414/152124) while in subpopulation SAS AF= 0.0265 (128/4830). AF 95% confidence interval is 0.0228. There are 17 homozygotes in gnomad4. There are 666 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDLIM3	NM_014476.6	c.*12C>T		3_prime_UTR_variant	8/8	ENST00000284767.12	NP_055291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDLIM3	ENST00000284767.12	c.*12C>T		3_prime_UTR_variant	8/8	5	NM_014476.6	ENSP00000284767	A1
	ENST00000671042.1	n.518-4219G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1414 AN: 152006 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00233

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0111 AC: 2799 AN: 251472 Hom.: 30 AF XY: 0.0119 AC XY: 1621 AN XY: 135912

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.0343

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0235

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0119 AC: 17351 AN: 1461546 Hom.: 147 Cov.: 30 AF XY: 0.0122 AC XY: 8891 AN XY: 727108

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00615

Gnomad4 ASJ exome AF: 0.0339

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0236

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00930 AC: 1414 AN: 152124 Hom.: 17 Cov.: 33 AF XY: 0.00896 AC XY: 666 AN XY: 74368

Gnomad4 AFR AF: 0.00234

Gnomad4 AMR AF: 0.00882

Gnomad4 ASJ AF: 0.0320

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0265

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0131 Hom.: 3

Bravo AF: 0.00856

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	*12C>T in exon 8 of PDLIM3: This variant is not expected to have clinical signif icance because it has been identified in 1.3% (111/8600) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs8315). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs8315; hg19: chr4-186423436;