rs61736238

chr11-119344876-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031433.4(MFRP):c.770G>A(p.Arg257His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,613,140 control chromosomes in the GnomAD database, including 383 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R257R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (201 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (182 hom.)
• Consequence: MFRP NM_031433.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003878
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.03

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015755296).
• BP6: Variant 11-119344876-C-T is Benign according to our data. Variant chr11-119344876-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 198271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119344876-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFRP	NM_031433.4	c.770G>A	p.Arg257His	missense_variant, splice_region_variant	6/15	ENST00000619721.6
C1QTNF5	NM_015645.5	c.-1867G>A		splice_region_variant, 5_prime_UTR_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFRP	ENST00000619721.6	c.770G>A	p.Arg257His	missense_variant, splice_region_variant	6/15	1	NM_031433.4	P1
MFRP	ENST00000360167.4	c.770G>A	p.Arg257His	missense_variant, splice_region_variant	6/10	2
MFRP	ENST00000529147.2	n.733G>A		splice_region_variant, non_coding_transcript_exon_variant	5/6	5
MFRP	ENST00000634542.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4261 AN: 152122 Hom.: 196 Cov.: 33

Gnomad AFR AF: 0.0968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.00843 AC: 2061 AN: 244618 Hom.: 77 AF XY: 0.00660 AC XY: 878 AN XY: 132966

Gnomad AFR exome AF: 0.0984

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00752

Gnomad SAS exome AF: 0.00429

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000268

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00323 AC: 4715 AN: 1460900 Hom.: 182 Cov.: 34 AF XY: 0.00290 AC XY: 2107 AN XY: 726714

Gnomad4 AFR exome AF: 0.0970

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00776

Gnomad4 SAS exome AF: 0.00407

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00687

GnomAD4 genome AF: 0.0282 AC: 4295 AN: 152240 Hom.: 201 Cov.: 33 AF XY: 0.0269 AC XY: 2006 AN XY: 74438

Gnomad4 AFR AF: 0.0973

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00675

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.00628 Hom.: 67

Bravo AF: 0.0309

ESP6500AA AF: 0.0958 AC: 421

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0102 AC: 1238

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 23, 2015

- -

Retinal degeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Isolated microphthalmia 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 27884173, 18648522, 20981092) -

Late-onset retinal degeneration Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Benign	0.95
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.2	N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.99	T;T
Polyphen		0.0	B;.
Vest4		0.14
ClinPred		0.012	T
GERP RS		4.9
Varity_R		0.035
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0020
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: rs61736238; hg19: chr11-119215586;