rs770341402
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_031433.4(MFRP):c.397G>T(p.Glu133Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,752 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
MFRP
NM_031433.4 stop_gained
NM_031433.4 stop_gained
Scores
2
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3
Clinical Significance
Conservation
PhyloP100: 0.485
Genes affected
MFRP (HGNC:18121): (membrane frizzled-related protein) This gene encodes a member of the frizzled-related protein family. The encoded protein plays an important role in eye development and mutations in this gene have been associated with nanophthalmos, posterior microphthalmia, retinitis pigmentosa, foveoschisis, and optic disc drusen. The protein is encoded by a bicistronic transcript which also encodes C1q and tumor necrosis factor related protein 5 (C1QTNF5). [provided by RefSeq, Jun 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-119345803-C-A is Pathogenic according to our data. Variant chr11-119345803-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 468921.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MFRP | NM_031433.4 | c.397G>T | p.Glu133Ter | stop_gained | 4/15 | ENST00000619721.6 | |
C1QTNF5 | NM_015645.5 | c.-2240G>T | 5_prime_UTR_variant | 4/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MFRP | ENST00000619721.6 | c.397G>T | p.Glu133Ter | stop_gained | 4/15 | 1 | NM_031433.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247860Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134302
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GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461568Hom.: 0 Cov.: 37 AF XY: 0.0000316 AC XY: 23AN XY: 727066
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Isolated microphthalmia 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2021 | This sequence change creates a premature translational stop signal (p.Glu133*) 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). This variant is present in population databases (rs770341402, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MFRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 468921). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at