rs145319149

Positions:

• chr11-119343926-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_031433.4(MFRP):​c.1014C>A​(p.Ser338Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,508 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: MFRP NM_031433.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 0.446

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010508984).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFRP	NM_031433.4	c.1014C>A	p.Ser338Arg	missense_variant	9/15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5	c.-1623C>A		5_prime_UTR_variant	9/15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6	c.1014C>A	p.Ser338Arg	missense_variant	9/15	1	NM_031433.4	ENSP00000481824.1
MFRP	ENST00000360167.4	c.898+706C>A		intron_variant		2		ENSP00000353291.4

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 151956 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00100 AC: 250 AN: 248770 Hom.: 0 AF XY: 0.00105 AC XY: 142 AN XY: 134708

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00144 AC: 2107 AN: 1461552 Hom.: 2 Cov.: 32 AF XY: 0.00143 AC XY: 1040 AN XY: 727068

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00111

Gnomad4 NFE exome AF: 0.00170

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00118 AC: 180 AN: 151956 Hom.: 0 Cov.: 31 AF XY: 0.00106 AC XY: 79 AN XY: 74188

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00132 Hom.: 2

Bravo AF: 0.00123

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000997 AC: 121

EpiCase AF: 0.00136

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2013	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Isolated microphthalmia 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 338 of the MFRP protein (p.Ser338Arg). This variant is present in population databases (rs145319149, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 167294). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MFRP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinal degeneration Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

MFRP-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Late-onset retinal degeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.87
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.64	N
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.46		Loss of catalytic residue at G336 (P = 0.1745);
MVP		0.11
ClinPred		0.00049	T
GERP RS		2.3
Varity_R		0.048
gMVP		0.62

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: rs145319149; hg19: chr11-119214636;