NM_014476.6:c.794A>G

Variant names:

• chr4-185504586-T-C
• rs750061720
• NM_014476.6:c.794A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014476.6(PDLIM3):​c.794A>G​(p.Asp265Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,460,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PDLIM3 NM_014476.6 missense, splice_region
• Scores: Splicing: ADA: 0.001312
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.39
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14253211).

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.794A>G	p.Asp265Gly	missense splice_region	Exon 7 of 8	NP_055291.2
	PDLIM3	NM_001114107.5		c.650A>G	p.Asp217Gly	missense splice_region	Exon 6 of 7	NP_001107579.1
	PDLIM3	NM_001257962.2		c.530A>G	p.Asp177Gly	missense splice_region	Exon 6 of 7	NP_001244891.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM3	ENST00000284767.12	TSL:5 MANE Select	c.794A>G	p.Asp265Gly	missense splice_region	Exon 7 of 8	ENSP00000284767.8
	PDLIM3	ENST00000284771.7	TSL:1	c.650A>G	p.Asp217Gly	missense splice_region	Exon 6 of 7	ENSP00000284771.6
	PDLIM3	ENST00000284770.10	TSL:1	c.293A>G	p.Asp98Gly	missense splice_region	Exon 4 of 5	ENSP00000284770.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250738 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460924 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726778

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111268

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.030	N
PhyloP100		5.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.091
Sift	Benign	0.64	T
Sift4G	Benign	0.47	T
Polyphen		0.35	B
Vest4		0.34
MutPred		0.40		Gain of glycosylation at S264 (P = 0.0092)
MVP		0.63
MPC		0.21
ClinPred		0.58	D
GERP RS		5.4
Varity_R		0.17
gMVP		0.38
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.014
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: rs750061720; hg19: chr4-186425740;