rs145881139

chr11-119342609-C-Achr11-119342609-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031433.4(MFRP):c.1374G>T(p.Leu458Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00817 in 1,613,338 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (74 hom.)
• Consequence: MFRP NM_031433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0310

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=0.005207181).
• BP6: Variant 11-119342609-C-A is Benign according to our data. Variant chr11-119342609-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 261961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119342609-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00891 (1356/152216) while in subpopulation AMR AF= 0.0117 (179/15302). AF 95% confidence interval is 0.0103. There are 13 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFRP	NM_031433.4	c.1374G>T	p.Leu458Phe	missense_variant	11/15	ENST00000619721.6
C1QTNF5	NM_015645.5	c.-1263G>T		5_prime_UTR_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFRP	ENST00000619721.6	c.1374G>T	p.Leu458Phe	missense_variant	11/15	1	NM_031433.4	P1
MFRP	ENST00000360167.4	c.1148G>T	p.Cys383Phe	missense_variant	9/10	2
MFRP	ENST00000449574.7	c.246G>T	p.Leu82Phe	missense_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152098 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00818 AC: 2008 AN: 245552 Hom.: 14 AF XY: 0.00839 AC XY: 1122 AN XY: 133652

Gnomad AFR exome AF: 0.00567

Gnomad AMR exome AF: 0.00703

Gnomad ASJ exome AF: 0.0293

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00845

Gnomad FIN exome AF: 0.00214

Gnomad NFE exome AF: 0.00929

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00809 AC: 11817 AN: 1461122 Hom.: 74 Cov.: 33 AF XY: 0.00829 AC XY: 6024 AN XY: 726840

Gnomad4 AFR exome AF: 0.00642

Gnomad4 AMR exome AF: 0.00810

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00772

Gnomad4 FIN exome AF: 0.00216

Gnomad4 NFE exome AF: 0.00800

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.00891 AC: 1356 AN: 152216 Hom.: 13 Cov.: 33 AF XY: 0.00829 AC XY: 617 AN XY: 74408

Gnomad4 AFR AF: 0.00645

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0108 Hom.: 21

Bravo AF: 0.00956

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00659 AC: 29

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.00822 AC: 997

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

C1QTNF5: BS1, BS2; MFRP: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.11
Sift	Benign	0.039	D
Sift4G	Uncertain	0.043	D
Vest4		0.37
MVP		0.35
ClinPred		0.029	T
GERP RS		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs145881139; hg19: chr11-119213319; COSMIC: COSV99070467; COSMIC: COSV99070467;