rs4639950

Variant names:

• chr11-119345845-T-C
• rs4639950
• NM_031433.4:c.355A>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.355A>G​(p.Ile119Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,613,524 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (67 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (52 hom.)
• Consequence: MFRP NM_031433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0230
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026126802).
• BP6: Variant 11-119345845-T-C is Benign according to our data. Variant chr11-119345845-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 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.355A>G	p.Ile119Val	missense	Exon 4 of 15	NP_113621.1	Q9BY79-1
	C1QTNF5	NM_015645.5		c.-2282A>G		5_prime_UTR	Exon 4 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.355A>G	p.Ile119Val	missense	Exon 4 of 15	ENSP00000481824.1	Q9BY79-1
	MFRP	ENST00000360167.4	TSL:2	c.355A>G	p.Ile119Val	missense	Exon 4 of 10	ENSP00000353291.4	Q9BY79-2
	MFRP	ENST00000526059.1	TSL:3	n.513A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2233 AN: 151730 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00551

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00405 AC: 1003 AN: 247844 AF XY: 0.00284

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000724

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00159 AC: 2328 AN: 1461676 Hom.: 52 Cov.: 36 AF XY: 0.00138 AC XY: 1002 AN XY: 727118

African (AFR) AF: 0.0546 AC: 1828 AN: 33480

American (AMR) AF: 0.00306 AC: 137 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111966

Other (OTH) AF: 0.00440 AC: 266 AN: 60390

GnomAD4 genome AF: 0.0147 AC: 2238 AN: 151848 Hom.: 67 Cov.: 32 AF XY: 0.0147 AC XY: 1091 AN XY: 74234

African (AFR) AF: 0.0512 AC: 2119 AN: 41382

American (AMR) AF: 0.00550 AC: 84 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67928

Other (OTH) AF: 0.0119 AC: 25 AN: 2108

Alfa AF: 0.00549 Hom.: 62

Bravo AF: 0.0171

ESP6500AA AF: 0.0480 AC: 211

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00493 AC: 599

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Isolated microphthalmia 5 (2)
-	-	1	Late-onset retinal degeneration (1)
-	-	1	Nanophthalmos 2;C1970236:Isolated microphthalmia 5 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.6
DANN	Benign	0.78
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.023
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.042
Sift	Benign	0.31	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.11
MVP		0.28
ClinPred		0.0080	T
GERP RS		2.8
Varity_R		0.018
gMVP		0.24
Mutation Taster		=98/2	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: rs4639950; hg19: chr11-119216555; COSMIC: COSV64128619; COSMIC: COSV64128619;