NM_005262.3:c.199delC
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_005262.3(GFER):c.199delC(p.Arg67GlyfsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,541,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005262.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GFER | ENST00000248114.7 | c.199delC | p.Arg67GlyfsTer83 | frameshift_variant | Exon 1 of 3 | 1 | NM_005262.3 | ENSP00000248114.6 | ||
GFER | ENST00000565658.1 | n.86delC | non_coding_transcript_exon_variant | Exon 1 of 2 | 1 | |||||
GFER | ENST00000561710.1 | c.160delC | p.Arg54GlyfsTer83 | frameshift_variant | Exon 1 of 2 | 2 | ENSP00000456189.1 | |||
GFER | ENST00000569451.1 | c.199delC | p.Arg67GlyfsTer74 | frameshift_variant | Exon 1 of 2 | 5 | ENSP00000456432.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152056Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000443 AC: 6AN: 135570Hom.: 0 AF XY: 0.0000672 AC XY: 5AN XY: 74442
GnomAD4 exome AF: 0.000264 AC: 367AN: 1389554Hom.: 0 Cov.: 32 AF XY: 0.000271 AC XY: 186AN XY: 685898
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74402
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
This sequence change creates a premature translational stop signal (p.Arg67Glyfs*83) in the GFER gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 139 amino acid(s) of the GFER protein. This variant is present in population databases (rs747241374, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of GFER-related condition (PMID: 34732400). ClinVar contains an entry for this variant (Variation ID: 214476). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
c.199delC:p.Arg67GlyfsX83 (R67GfsX83) in exon 1 of the GFER gene (NM_005262.2). The normal sequence with the base that is deleted in braces is: CTCC{C}GGAG. The c.199delC variant in the GFER gene causes a frameshift starting with codon Arginine 67, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 83 of the new reading frame, denoted p.Arg67GlyfsX83. It has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay; however, to date no frameshift variants have been reported in the GFER gene. The c.199delC variant is a good candidate for a pathogenic variant, but the possibility it may be a rare benign variant cannot be excluded. -
Mitochondrial disease Pathogenic:1
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Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at