chr11-119346578-C-T

Variant names:

• chr11-119346578-C-T
• rs883246
• NM_031433.4:c.-65G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

C1QTNF5 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• late-onset retinal degeneration

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 302986.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFRP	NM_031433.4	MANE Select	c.-65G>A		5_prime_UTR	Exon 1 of 15	NP_113621.1	Q9BY79-1
	C1QTNF5	NM_015645.5		c.-2701G>A		5_prime_UTR	Exon 1 of 15	NP_056460.1	Q9BXJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFRP	ENST00000619721.6	TSL:1 MANE Select	c.-65G>A		5_prime_UTR	Exon 1 of 15	ENSP00000481824.1	Q9BY79-1
	MFRP	ENST00000360167.4	TSL:2	c.-65G>A		5_prime_UTR	Exon 1 of 10	ENSP00000353291.4	Q9BY79-2
	MFRP	ENST00000526059.1	TSL:3	n.40G>A		non_coding_transcript_exon	Exon 1 of 3

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

African (AFR) AF: 0.00288 AC: 92 AN: 31910

American (AMR) AF: 0.00270 AC: 120 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.0301 AC: 772 AN: 25648

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39354

South Asian (SAS) AF: 0.00295 AC: 250 AN: 84634

European-Finnish (FIN) AF: 0.0110 AC: 583 AN: 53038

Middle Eastern (MID) AF: 0.00750 AC: 35 AN: 4668

European-Non Finnish (NFE) AF: 0.00894 AC: 9338 AN: 1044700

Other (OTH) AF: 0.00858 AC: 496 AN: 57780

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

African (AFR) AF: 0.00267 AC: 111 AN: 41542

American (AMR) AF: 0.00229 AC: 35 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4824

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00838 AC: 570 AN: 68012

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00706 Hom.: 3

Bravo AF: 0.00574

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.89
PhyloP100		-1.0
PromoterAI		-0.0024	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs883246; hg19: chr11-119217288;