11-119345562-TG-TGG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_031433.4(MFRP):c.498dupC(p.Asn167GlnfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_031433.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MFRP | NM_031433.4 | c.498dupC | p.Asn167GlnfsTer34 | frameshift_variant | Exon 5 of 15 | ENST00000619721.6 | NP_113621.1 | |
C1QTNF5 | NM_015645.5 | c.-2139dupC | 5_prime_UTR_variant | Exon 5 of 15 | NP_056460.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 1AN: 152020Hom.: 0 Cov.: 33 FAILED QC
GnomAD3 exomes AF: 0.0000604 AC: 15AN: 248178Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134620
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461660Hom.: 0 Cov.: 57 AF XY: 0.0000248 AC XY: 18AN XY: 727120
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
Isolated microphthalmia 5 Pathogenic:3
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.022%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 2014036, 25596310). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000582 /PMID: 2574153 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 17935162, 25596310, 26481238). Different missense changes at the same codon (p.Arg261Gly, p.Arg261Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102832 /PMID: 26666653, 7556322). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
This sequence change creates a premature translational stop signal (p.Asn167Glnfs*34) in the MFRP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MFRP are known to be pathogenic (PMID: 12140190, 15976030, 20361016). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal recessive nanophthalmos and retinal dystrophy (PMID: 17167404, 23742260). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.498_499insC, P165fsX198. ClinVar contains an entry for this variant (Variation ID: 4478). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17167404, 23742260, 31992737, 31589614) -
Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at