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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MFRP
NM_031433.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.33
Variant links:
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]
C1QTNF5 (HGNC:14344): (C1q and TNF related 5) This gene encodes a member of a family of proteins that function as components of basement membranes and may play a role in cell adhesion. Mutations in this gene have been associated with late-onset retinal degeneration. The protein may be encoded by either a bicistronic transcript including sequence from the upstream membrane frizzled-related protein gene (MFRP), or by a monocistronic transcript expressed from an internal promoter. [provided by RefSeq, Jun 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 11-119345562-T-TG is Pathogenic according to our data. Variant chr11-119345562-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 4478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MFRPNM_031433.4 linkc.498dupC p.Asn167GlnfsTer34 frameshift_variant Exon 5 of 15 ENST00000619721.6 NP_113621.1 Q9BY79-1
C1QTNF5NM_015645.5 linkc.-2139dupC 5_prime_UTR_variant Exon 5 of 15 NP_056460.1 Q9BXJ0A0A024R3F8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MFRPENST00000619721.6 linkc.498dupC p.Asn167GlnfsTer34 frameshift_variant Exon 5 of 15 1 NM_031433.4 ENSP00000481824.1 Q9BY79-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
1
AN:
152020
Hom.:
0
Cov.:
33
FAILED QC
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000604
AC:
15
AN:
248178
Hom.:
0
AF XY:
0.0000223
AC XY:
3
AN XY:
134620
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000904
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000281
AC:
41
AN:
1461660
Hom.:
0
Cov.:
57
AF XY:
0.0000248
AC XY:
18
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.0000939
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000657
AC:
1
AN:
152138
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Isolated microphthalmia 5 Pathogenic:3
Nov 02, 2023
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nov 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 04, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:1
Apr 09, 2020
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jan 01, 2023
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776596; hg19: chr11-119216272; API