rs145881139

Variant names:

• chr11-119342609-C-A
• rs145881139
• NM_031433.4:c.1374G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-119342609-C-A
• chr11-119342609-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031433.4(MFRP):​c.1374G>T​(p.Leu458Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00817 in 1,613,338 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (74 hom.)
• Consequence: MFRP NM_031433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0310
• Publications: 9 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=0.005207181).
• BP6: Variant 11-119342609-C-A is Benign according to our data. Variant chr11-119342609-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00891 (1356/152216) while in subpopulation AMR AF = 0.0117 (179/15302). AF 95% confidence interval is 0.0103. There are 13 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1374G>T	p.Leu458Phe	missense	Exon 11 of 15	NP_113621.1	Q9BY79-1
	C1QTNF5	NM_015645.5		c.-1263G>T		5_prime_UTR	Exon 11 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.1374G>T	p.Leu458Phe	missense	Exon 11 of 15	ENSP00000481824.1	Q9BY79-1
	MFRP	ENST00000360167.4	TSL:2	c.1148G>T	p.Cys383Phe	missense	Exon 9 of 10	ENSP00000353291.4	Q9BY79-2
	MFRP	ENST00000449574.7	TSL:5	c.243G>T	p.Leu81Phe	missense	Exon 2 of 4	ENSP00000391664.3	A0A0X1KG76

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152098 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00818 AC: 2008 AN: 245552 AF XY: 0.00839

Gnomad AFR exome AF: 0.00567

Gnomad AMR exome AF: 0.00703

Gnomad ASJ exome AF: 0.0293

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00214

Gnomad NFE exome AF: 0.00929

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00809 AC: 11817 AN: 1461122 Hom.: 74 Cov.: 33 AF XY: 0.00829 AC XY: 6024 AN XY: 726840

African (AFR) AF: 0.00642 AC: 215 AN: 33480

American (AMR) AF: 0.00810 AC: 362 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 721 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00772 AC: 666 AN: 86240

European-Finnish (FIN) AF: 0.00216 AC: 114 AN: 52886

Middle Eastern (MID) AF: 0.0314 AC: 181 AN: 5766

European-Non Finnish (NFE) AF: 0.00800 AC: 8900 AN: 1111894

Other (OTH) AF: 0.0109 AC: 657 AN: 60358

GnomAD4 genome AF: 0.00891 AC: 1356 AN: 152216 Hom.: 13 Cov.: 33 AF XY: 0.00829 AC XY: 617 AN XY: 74408

African (AFR) AF: 0.00645 AC: 268 AN: 41540

American (AMR) AF: 0.0117 AC: 179 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 107 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4828

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10620

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 693 AN: 67970

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0101 Hom.: 26

Bravo AF: 0.00956

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00659 AC: 29

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.00822 AC: 997

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0114

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Isolated microphthalmia 5 (1)
-	-	1	not specified (1)
-	-	1	Retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.86	T
PhyloP100		-0.031
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.11
Sift	Benign	0.039	D
Sift4G	Uncertain	0.043	D
Vest4		0.37
MVP		0.35
ClinPred		0.029	T
GERP RS		2.0
PromoterAI		-0.013	Neutral
Varity_R		0.19
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs145881139; hg19: chr11-119213319; COSMIC: COSV99070467; COSMIC: COSV99070467;