rs61736238

Variant names:

• chr11-119344876-C-T
• rs61736238
• NM_031433.4:c.770G>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.770G>A​(p.Arg257His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,613,140 control chromosomes in the GnomAD database, including 383 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (201 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (182 hom.)
• Consequence: MFRP NM_031433.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003878
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.03
• Publications: 7 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 (MetaRNN=0.0015755296).
• BP6: Variant 11-119344876-C-T is Benign according to our data. Variant chr11-119344876-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0948 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.770G>A	p.Arg257His	missense splice_region	Exon 6 of 15	NP_113621.1
	C1QTNF5	NM_015645.5		c.-1867G>A		splice_region	Exon 6 of 15	NP_056460.1
	C1QTNF5	NM_015645.5		c.-1867G>A		5_prime_UTR	Exon 6 of 15	NP_056460.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFRP	ENST00000619721.6	TSL:1 MANE Select	c.770G>A	p.Arg257His	missense splice_region	Exon 6 of 15	ENSP00000481824.1
	MFRP	ENST00000360167.4	TSL:2	c.770G>A	p.Arg257His	missense splice_region	Exon 6 of 10	ENSP00000353291.4
	MFRP	ENST00000529147.2	TSL:5	n.733G>A		splice_region non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4261 AN: 152122 Hom.: 196 Cov.: 33

Gnomad AFR AF: 0.0968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00843 AC: 2061 AN: 244618 AF XY: 0.00660

Gnomad AFR exome AF: 0.0984

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00752

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000268

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00323 AC: 4715 AN: 1460900 Hom.: 182 Cov.: 34 AF XY: 0.00290 AC XY: 2107 AN XY: 726714

African (AFR) AF: 0.0970 AC: 3248 AN: 33480

American (AMR) AF: 0.00539 AC: 241 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26128

East Asian (EAS) AF: 0.00776 AC: 308 AN: 39694

South Asian (SAS) AF: 0.00407 AC: 351 AN: 86222

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52624

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1111934

Other (OTH) AF: 0.00687 AC: 415 AN: 60366

GnomAD4 genome AF: 0.0282 AC: 4295 AN: 152240 Hom.: 201 Cov.: 33 AF XY: 0.0269 AC XY: 2006 AN XY: 74438

African (AFR) AF: 0.0973 AC: 4039 AN: 41494

American (AMR) AF: 0.00869 AC: 133 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00675 AC: 35 AN: 5184

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68024

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.0125 Hom.: 195

Bravo AF: 0.0309

ESP6500AA AF: 0.0958 AC: 421

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0102 AC: 1238

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

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	Late-onset retinal degeneration (1)
-	-	1	not specified (1)
-	-	1	Retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.2	N
PhyloP100		3.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.10
Sift	Benign	0.73	T
Sift4G	Benign	0.99	T
Polyphen		0.0	B
Vest4		0.14
ClinPred		0.012	T
GERP RS		4.9
Varity_R		0.035
gMVP		0.21
Mutation Taster		=292/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0020
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: rs61736238; hg19: chr11-119215586;