chr4-94575715-C-A

Variant names:

• chr4-94575715-C-A
• rs1224238557
• NM_006457.5:c.391C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006457.5(PDLIM5):​c.391C>A​(p.Pro131Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDLIM5 NM_006457.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.84
• Publications: 0 publications found

Genes affected

PDLIM5 (HGNC:17468): (PDZ and LIM domain 5) This gene encodes a member of a family of proteins that possess a 100-amino acid PDZ domain at the N terminus and one to three LIM domains at the C-terminus. This family member functions as a scaffold protein that tethers protein kinases to the Z-disk in striated muscles. It is thought to function in cardiomyocyte expansion and in restraining postsynaptic growth of excitatory synapses. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006457.5. 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
	PDLIM5	NM_006457.5	MANE Select	c.391C>A	p.Pro131Thr	missense	Exon 5 of 13	NP_006448.5	Q96HC4-1
	PDLIM5	NM_001256428.2		c.25C>A	p.Pro9Thr	missense	Exon 4 of 12	NP_001243357.2
	PDLIM5	NM_001256426.2		c.292-228C>A		intron	N/A	NP_001243355.2	Q96HC4-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDLIM5	ENST00000317968.9	TSL:1 MANE Select	c.391C>A	p.Pro131Thr	missense	Exon 5 of 13	ENSP00000321746.4	Q96HC4-1
	PDLIM5	ENST00000615540.4	TSL:1	c.292-228C>A		intron	N/A	ENSP00000480359.1	Q96HC4-6
	PDLIM5	ENST00000542407.5	TSL:1	c.292-228C>A		intron	N/A	ENSP00000442187.2	Q96HC4-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.8
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.43		Gain of phosphorylation at P131 (P = 0.0327)
MVP		0.85
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.58
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs1224238557; hg19: chr4-95496866;