rs587776596

chr11-119345562-TG-Tchr11-119345562-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_031433.4(MFRP):c.498del(p.Asn167ThrfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P166P) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: MFRP NM_031433.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.33

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:):

ACMG classification

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-TG-T is Pathogenic according to our data. Variant chr11-119345562-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 4476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119345562-TG-T is described in Lovd as [Pathogenic]. Variant chr11-119345562-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr11-119345562-TG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFRP	NM_031433.4	c.498del	p.Asn167ThrfsTer25	frameshift_variant	5/15	ENST00000619721.6
C1QTNF5	NM_015645.5	c.-2139del		5_prime_UTR_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFRP	ENST00000619721.6	c.498del	p.Asn167ThrfsTer25	frameshift_variant	5/15	1	NM_031433.4	P1
MFRP	ENST00000360167.4	c.498del	p.Asn167ThrfsTer25	frameshift_variant	5/10	2
MFRP	ENST00000529147.2	n.461del		non_coding_transcript_exon_variant	4/6	5
MFRP	ENST00000634542.1	c.*89del		3_prime_UTR_variant, NMD_transcript_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000129 AC: 32 AN: 248178 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134620

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000698 AC: 102 AN: 1461686 Hom.: 0 Cov.: 57 AF XY: 0.0000633 AC XY: 46 AN XY: 727136

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74370

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000223

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nanophthalmos 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Isolated microphthalmia 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	This sequence change creates a premature translational stop signal (p.Asn167Thrfs*25) 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 (rs587776596, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with posterior microphthalmos/nanophthalmos and retinal dystrophy in a family, and has been observed in several affected individuals (PMID: 19753314, 23112574, 23143909). It has also been observed to segregate with disease in related individuals. This variant is also known as c.492delC, p.P166fs*26, and p.P166fs*190. ClinVar contains an entry for this variant (Variation ID: 4476). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

MFRP-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2023

The MFRP c.498delC variant is predicted to result in a frameshift and premature protein termination (p.Pro166Profs*26). This variant has been reported in the homozygous and compound heterozygous states in individuals with nanophthalmos or retinal dystrophy (reported as 492delC in Sundin et al. 2005. PubMed ID: 15976030; Kannabiran et al. 2012. PubMed ID: 22605927; Guo et al. 2019. PubMed ID: 31266062; Prasov et al. 2020. PubMed ID: 33203948). This variant is reported in 0.042% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-119216272-TG-T). Frameshift variants in MFRP are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/4476). Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs587776596; hg19: chr11-119216272;