chr4-185523375-T-A

Variant names:

• chr4-185523375-T-A
• rs199476400
• NM_014476.6:c.317A>T

Variant summary

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

The NM_014476.6(PDLIM3):​c.317A>T​(p.Glu106Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E106A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDLIM3 NM_014476.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.02
• 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:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDLIM3	NM_014476.6	c.317A>T	p.Glu106Val	missense_variant	Exon 3 of 8	ENST00000284767.12	NP_055291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDLIM3	ENST00000284767.12	c.317A>T	p.Glu106Val	missense_variant	Exon 3 of 8	5	NM_014476.6	ENSP00000284767.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	2.0	M;M;.
PhyloP100		7.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D;D;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D;D;.
Sift4G	Benign	0.20	T;T;.
Polyphen		0.99	D;D;.
Vest4		0.69
MutPred		0.42		Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);
MVP		0.84
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.63
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199476400; hg19: chr4-186444529;