rs4635850

chr4-185502483-G-Achr4-185502483-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014476.6(PDLIM3):c.906C>T(p.Val302=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 1,613,280 control chromosomes in the GnomAD database, including 549,789 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (41055 hom., cov: 32)
  • Exomes 𝑓: 0.83 (508734 hom.)
• Consequence: PDLIM3 NM_014476.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0005494
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.57

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-185502483-G-A is Benign according to our data. Variant chr4-185502483-G-A is described in ClinVar as [Benign]. Clinvar id is 138675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-185502483-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDLIM3	NM_014476.6	c.906C>T	p.Val302=	splice_region_variant, synonymous_variant	8/8	ENST00000284767.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDLIM3	ENST00000284767.12	c.906C>T	p.Val302=	splice_region_variant, synonymous_variant	8/8	5	NM_014476.6	A1
	ENST00000671042.1	n.518-4018G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107232 AN: 152010 Hom.: 41049 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.880

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.868

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.705

GnomAD3 exomes AF: 0.787 AC: 197765 AN: 251144 Hom.: 79766 AF XY: 0.796 AC XY: 108032 AN XY: 135792

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.751

Gnomad ASJ exome AF: 0.750

Gnomad EAS exome AF: 0.811

Gnomad SAS exome AF: 0.747

Gnomad FIN exome AF: 0.874

Gnomad NFE exome AF: 0.852

Gnomad OTH exome AF: 0.794

GnomAD4 exome AF: 0.830 AC: 1212881 AN: 1461154 Hom.: 508734 Cov.: 46 AF XY: 0.829 AC XY: 602772 AN XY: 726952

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.749

Gnomad4 ASJ exome AF: 0.753

Gnomad4 EAS exome AF: 0.820

Gnomad4 SAS exome AF: 0.752

Gnomad4 FIN exome AF: 0.877

Gnomad4 NFE exome AF: 0.856

Gnomad4 OTH exome AF: 0.791

GnomAD4 genome AF: 0.705 AC: 107263 AN: 152126 Hom.: 41055 Cov.: 32 AF XY: 0.708 AC XY: 52662 AN XY: 74372

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.756

Gnomad4 ASJ AF: 0.748

Gnomad4 EAS AF: 0.814

Gnomad4 SAS AF: 0.728

Gnomad4 FIN AF: 0.868

Gnomad4 NFE AF: 0.852

Gnomad4 OTH AF: 0.708

Alfa AF: 0.814 Hom.: 85485

Bravo AF: 0.682

Asia WGS AF: 0.734 AC: 2551 AN: 3478

EpiCase AF: 0.842

EpiControl AF: 0.842

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	This is a RefSeq error. The reference base (c.906C) is the minor allele. This al lele (C) has been identified in 15% (1260/8600) of European American chromosomes and 61% (2685/4406) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1134008) and thus meets c riteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2019	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.069
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00055
dbscSNV1_RF	Benign	0.088
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: rs4635850; hg19: chr4-186423637; COSMIC: COSV52977614; COSMIC: COSV52977614;