chr5-177496469-C-T

Variant names:

• chr5-177496469-C-T
• NM_005451.5:c.44G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005451.5(PDLIM7):​c.44G>A​(p.Gly15Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PDLIM7 NM_005451.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.40

Genes affected

PDLIM7 (HGNC:22958): (PDZ and LIM domain 7) The protein encoded by this gene is representative of a family of proteins composed of conserved PDZ and LIM domains. LIM domains are proposed to function in protein-protein recognition in a variety of contexts including gene transcription and development and in cytoskeletal interaction. The LIM domains of this protein bind to protein kinases, whereas the PDZ domain binds to actin filaments. The gene product is involved in the assembly of an actin filament-associated complex essential for transmission of ret/ptc2 mitogenic signaling. The biological function is likely to be that of an adapter, with the PDZ domain localizing the LIM-binding proteins to actin filaments of both skeletal muscle and nonmuscle tissues. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

PDLIM7-AS1 (HGNC:41004): (PDLIM7 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDLIM7	NM_005451.5	c.44G>A	p.Gly15Asp	missense_variant	Exon 2 of 13	ENST00000355841.7	NP_005442.2
PDLIM7	NM_203352.3	c.44G>A	p.Gly15Asp	missense_variant	Exon 2 of 13		NP_976227.1
PDLIM7	NM_213636.3	c.44G>A	p.Gly15Asp	missense_variant	Exon 2 of 8		NP_998801.1
PDLIM7	NR_103804.2	n.132G>A		non_coding_transcript_exon_variant	Exon 2 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDLIM7	ENST00000355841.7	c.44G>A	p.Gly15Asp	missense_variant	Exon 2 of 13	1	NM_005451.5	ENSP00000348099.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453034 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 722610

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44G>A (p.G15D) alteration is located in exon 2 (coding exon 1) of the PDLIM7 gene. This alteration results from a G to A substitution at nucleotide position 44, causing the glycine (G) at amino acid position 15 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.;.;.;.;T;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	4.4	H;H;H;.;H;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;.
Polyphen		1.0	D;D;D;.;D;.;.;.
Vest4		0.93
MutPred		0.96		Loss of catalytic residue at P11 (P = 0.1774);Loss of catalytic residue at P11 (P = 0.1774);Loss of catalytic residue at P11 (P = 0.1774);Loss of catalytic residue at P11 (P = 0.1774);Loss of catalytic residue at P11 (P = 0.1774);Loss of catalytic residue at P11 (P = 0.1774);Loss of catalytic residue at P11 (P = 0.1774);Loss of catalytic residue at P11 (P = 0.1774);
MVP		0.93
MPC		0.93
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-176923470;