rs4635850

Variant names:

• chr4-185502483-G-A
• rs4635850
• NM_014476.6:c.906C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-185502483-G-A
• chr4-185502483-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014476.6(PDLIM3):​c.906C>T​(p.Val302Val) 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:6
• Conservation: PhyloP100: -3.57
• Publications: 19 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: Benign. The variant received -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 VariationId is 138675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.906C>T	p.Val302Val	splice_region synonymous	Exon 8 of 8	NP_055291.2	Q53GG5-1
	PDLIM3	NM_001114107.5		c.762C>T	p.Val254Val	splice_region synonymous	Exon 7 of 7	NP_001107579.1	Q53GG5-2
	PDLIM3	NM_001257962.2		c.642C>T	p.Val214Val	splice_region synonymous	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.906C>T	p.Val302Val	splice_region synonymous	Exon 8 of 8	ENSP00000284767.8	Q53GG5-1
	PDLIM3	ENST00000284771.7	TSL:1	c.762C>T	p.Val254Val	splice_region synonymous	Exon 7 of 7	ENSP00000284771.6	Q53GG5-2
	PDLIM3	ENST00000284770.10	TSL:1	c.405C>T	p.Val135Val	splice_region synonymous	Exon 5 of 5	ENSP00000284770.5	A0A2U3TZH4

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

GnomAD2 exomes AF: 0.787 AC: 197765 AN: 251144 AF XY: 0.796

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 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

African (AFR) AF: 0.365 AC: 12215 AN: 33470

American (AMR) AF: 0.749 AC: 33499 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 19689 AN: 26132

East Asian (EAS) AF: 0.820 AC: 32537 AN: 39698

South Asian (SAS) AF: 0.752 AC: 64839 AN: 86242

European-Finnish (FIN) AF: 0.877 AC: 46844 AN: 53402

Middle Eastern (MID) AF: 0.679 AC: 3917 AN: 5768

European-Non Finnish (NFE) AF: 0.856 AC: 951614 AN: 1111362

Other (OTH) AF: 0.791 AC: 47727 AN: 60360

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

African (AFR) AF: 0.379 AC: 15712 AN: 41444

American (AMR) AF: 0.756 AC: 11563 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 2591 AN: 3466

East Asian (EAS) AF: 0.814 AC: 4196 AN: 5152

South Asian (SAS) AF: 0.728 AC: 3517 AN: 4830

European-Finnish (FIN) AF: 0.868 AC: 9205 AN: 10600

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.852 AC: 57981 AN: 68024

Other (OTH) AF: 0.708 AC: 1496 AN: 2114

Alfa AF: 0.802 Hom.: 178579

Bravo AF: 0.682

Asia WGS AF: 0.734 AC: 2551 AN: 3478

EpiCase AF: 0.842

EpiControl AF: 0.842

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.069
DANN	Benign	0.80
PhyloP100		-3.6
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4635850; hg19: chr4-186423637; COSMIC: COSV52977614; COSMIC: COSV52977614;