rs948414

Variant names:

• chr11-119344088-T-C
• rs948414
• NM_031433.4:c.976-124A>G

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.976-124A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,292,110 control chromosomes in the GnomAD database, including 247,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27378 hom., cov: 30)
  • Exomes 𝑓: 0.62 (219965 hom.)
• Consequence: MFRP NM_031433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.451
• Publications: 13 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-119344088-T-C is Benign according to our data. Variant chr11-119344088-T-C is described in ClinVar as Benign. ClinVar VariationId is 1231094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

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.976-124A>G		intron	N/A	NP_113621.1	Q9BY79-1
	C1QTNF5	NM_015645.5		c.-1661-124A>G		intron	N/A	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.976-124A>G		intron	N/A	ENSP00000481824.1	Q9BY79-1
	MFRP	ENST00000360167.4	TSL:2	c.898+544A>G		intron	N/A	ENSP00000353291.4	Q9BY79-2

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90384 AN: 151658 Hom.: 27345 Cov.: 30

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.600

GnomAD4 exome AF: 0.618 AC: 704731 AN: 1140332 Hom.: 219965 AF XY: 0.619 AC XY: 357634 AN XY: 577684

African (AFR) AF: 0.509 AC: 13978 AN: 27488

American (AMR) AF: 0.775 AC: 29635 AN: 38228

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 12039 AN: 23672

East Asian (EAS) AF: 0.573 AC: 20910 AN: 36518

South Asian (SAS) AF: 0.661 AC: 50989 AN: 77106

European-Finnish (FIN) AF: 0.716 AC: 27680 AN: 38672

Middle Eastern (MID) AF: 0.485 AC: 2112 AN: 4352

European-Non Finnish (NFE) AF: 0.613 AC: 517477 AN: 844498

Other (OTH) AF: 0.601 AC: 29911 AN: 49798

GnomAD4 genome AF: 0.596 AC: 90459 AN: 151778 Hom.: 27378 Cov.: 30 AF XY: 0.603 AC XY: 44763 AN XY: 74174

African (AFR) AF: 0.515 AC: 21284 AN: 41328

American (AMR) AF: 0.682 AC: 10418 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1770 AN: 3468

East Asian (EAS) AF: 0.513 AC: 2632 AN: 5126

South Asian (SAS) AF: 0.675 AC: 3244 AN: 4806

European-Finnish (FIN) AF: 0.720 AC: 7590 AN: 10546

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.613 AC: 41660 AN: 67922

Other (OTH) AF: 0.595 AC: 1256 AN: 2110

Alfa AF: 0.608 Hom.: 53397

Bravo AF: 0.587

Asia WGS AF: 0.601 AC: 2091 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.9
DANN	Benign	0.86
PhyloP100		-0.45
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs948414;

hg19: chr11-119214798;

COSMIC: COSV107466163;

COSMIC: COSV107466163;