NM_001448.3:c.1609C>T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_001448.3(GPC4):c.1609C>T(p.Gln537*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001448.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
GPC4-related disorder Pathogenic:1
The GPC4 c.1609C>T variant is predicted to result in premature protein termination (p.Gln537*). This variant is located within the terminal exon and is predicted to result in the deletion of the last 20 amino acids of GPC4. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At PreventionGenetics, this variant was found to have occurred de novo in a male individual with Keipert syndrome (internal data). Two nonsense variants, p.Glu496* and p.Gln506*, which are upstream in the terminal exon, have been reported to be causative for Keipert syndrome. It was proposed that the reduced protein stability as well as the loss of functionally critical N-linked glycosylation p.Asn514 and glycosylphosphatidylinositol anchor p.Ser529 are the underlying loss-of-function mechanism of the two nonsense variants (Amor et al. 2019. PubMed ID: 30982611). The c.1609C>T (p.Gln537*) variant is interpreted as likely pathogenic. -
Keipert syndrome Uncertain:1
The frameshift variant c.1609C>T(p.Gln537Ter) in GPC4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gln537Ter variant is novel (not in any individuals) in gnomAD exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. The nucleotide change c.1609C>T in GPC4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. However since this variant is present in the last exon functional studies will be required to prove protein truncation. Hence the variant is classified as Uncertain Significance (VUS). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.