chr5-177496469-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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

Scores

14
3
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.40
Variant links:
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)

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ACMG classification

Classification made for transcript

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
PDLIM7NM_005451.5 linkc.44G>A p.Gly15Asp missense_variant Exon 2 of 13 ENST00000355841.7 NP_005442.2 Q9NR12-1
PDLIM7NM_203352.3 linkc.44G>A p.Gly15Asp missense_variant Exon 2 of 13 NP_976227.1 Q9NR12-2
PDLIM7NM_213636.3 linkc.44G>A p.Gly15Asp missense_variant Exon 2 of 8 NP_998801.1 Q9NR12-6
PDLIM7NR_103804.2 linkn.132G>A non_coding_transcript_exon_variant Exon 2 of 13

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PDLIM7ENST00000355841.7 linkc.44G>A p.Gly15Asp missense_variant Exon 2 of 13 1 NM_005451.5 ENSP00000348099.2 Q9NR12-1

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
show subpopulations
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
LINK: link

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; API