rs12421909

Variant names:

• chr11-119345191-C-T
• rs12421909
• NM_031433.4:c.642-187G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031433.4(MFRP):​c.642-187G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0831 in 152,250 control chromosomes in the GnomAD database, including 812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.083 (812 hom., cov: 32)
• Consequence: MFRP NM_031433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.208
• Publications: 5 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):

• late-onset retinal degeneration

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-119345191-C-T is Benign according to our data. Variant chr11-119345191-C-T is described in ClinVar as Benign. ClinVar VariationId is 1272146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFRP	NM_031433.4	c.642-187G>A		intron_variant	Intron 5 of 14	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5	c.-1995-187G>A		intron_variant	Intron 5 of 14		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6	c.642-187G>A		intron_variant	Intron 5 of 14	1	NM_031433.4	ENSP00000481824.1
MFRP	ENST00000360167.4	c.642-187G>A		intron_variant	Intron 5 of 9	2		ENSP00000353291.4
MFRP	ENST00000529147.2	n.605-187G>A		intron_variant	Intron 4 of 5	5
MFRP	ENST00000634542.1	n.*233-187G>A		intron_variant	Intron 4 of 4	3		ENSP00000488979.1

Frequencies

GnomAD3 genomes AF: 0.0831 AC: 12642 AN: 152132 Hom.: 814 Cov.: 32

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.0675

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0630

Gnomad OTH AF: 0.0774

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0831 AC: 12652 AN: 152250 Hom.: 812 Cov.: 32 AF XY: 0.0893 AC XY: 6648 AN XY: 74426

African (AFR) AF: 0.0527 AC: 2189 AN: 41554

American (AMR) AF: 0.125 AC: 1911 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 495 AN: 3464

East Asian (EAS) AF: 0.293 AC: 1515 AN: 5174

South Asian (SAS) AF: 0.277 AC: 1334 AN: 4816

European-Finnish (FIN) AF: 0.0675 AC: 715 AN: 10598

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0630 AC: 4287 AN: 68024

Other (OTH) AF: 0.0808 AC: 171 AN: 2116

Alfa AF: 0.0757 Hom.: 321

Bravo AF: 0.0799

Asia WGS AF: 0.290 AC: 1005 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.1
DANN	Benign	0.60
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs12421909; hg19: chr11-119215901;