rs370475970
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_005262.3(GFER):c.586C>T(p.Arg196Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R196R) has been classified as Benign.
Frequency
Consequence
NM_005262.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GFER | NM_005262.3 | c.586C>T | p.Arg196Cys | missense_variant | 3/3 | ENST00000248114.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFER | ENST00000248114.7 | c.586C>T | p.Arg196Cys | missense_variant | 3/3 | 1 | NM_005262.3 | P1 | |
ENST00000654451.1 | n.935G>A | non_coding_transcript_exon_variant | 2/2 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250580Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135662
GnomAD4 exome AF: 0.0000377 AC: 55AN: 1460630Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26AN XY: 726622
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74362
ClinVar
Submissions by phenotype
Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome Uncertain:1Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 25, 2020 | A heterozygous missense variant was identified, NM_005262.2(GFER):c.586C>T in exon 3 of 3 of the GFER gene. This substitution is predicted to create a major amino acid change from an arginine to a cysteine at position 196 of the protein; NP_005253.3(GFER):p.(Arg196Cys). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the Erv1 / Alr family domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global population frequency of 0.004% (10 heterozygotes; 0 homozygotes) with a Latino sub-population frequency of 0.008%. An alternative residue change to histidine at the same location has also been reported in the gnomAD database at a frequency of 0.01%. This variant has been previously reported as pathogenic in a patient with mitochondrial disease (ClinVar, Martikainen, M. et al. (2017)). Based on information available at the time of curation, this variant has been classified as a VUS with POTENTIAL CLINICAL RELEVANCE. - |
Mitochondrial disease Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | Apr 07, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at