rs883246

Positions:

• chr11-119346578-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_031433.4(MFRP):​c.-65G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,538,402 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0063 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (67 hom.)
• Consequence: MFRP NM_031433.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -1.04

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]

MFRP (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 11-119346578-C-T is Benign according to our data. Variant chr11-119346578-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 302986.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00633 (963/152238) while in subpopulation NFE AF= 0.00838 (570/68012). AF 95% confidence interval is 0.00781. There are 4 homozygotes in gnomad4. There are 480 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFRP	NM_031433.4	c.-65G>A		5_prime_UTR_variant	1/15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5	c.-2701G>A		5_prime_UTR_variant	1/15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6	c.-65G>A		5_prime_UTR_variant	1/15	1	NM_031433.4	ENSP00000481824.1

Frequencies

GnomAD3 genomes AF: 0.00634 AC: 964 AN: 152120 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00838

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00843 AC: 11687 AN: 1386164 Hom.: 67 Cov.: 23 AF XY: 0.00836 AC XY: 5803 AN XY: 693768

Gnomad4 AFR exome AF: 0.00288

Gnomad4 AMR exome AF: 0.00270

Gnomad4 ASJ exome AF: 0.0301

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00295

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.00894

Gnomad4 OTH exome AF: 0.00858

GnomAD4 genome AF: 0.00633 AC: 963 AN: 152238 Hom.: 4 Cov.: 33 AF XY: 0.00645 AC XY: 480 AN XY: 74404

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.00838

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00715 Hom.: 3

Bravo AF: 0.00574

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	C1QTNF5: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Retinal degeneration Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.89

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: rs883246; hg19: chr11-119217288;