11-119342593-C-T

Variant names:

• chr11-119342593-C-T
• rs11217241
• NM_031433.4:c.1387+3G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_031433.4(MFRP):​c.1387+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,612,606 control chromosomes in the GnomAD database, including 16,943 homozygotes. In-silico tool predicts 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1434 hom., cov: 33)
  • Exomes 𝑓: 0.10 (15509 hom.)
• Consequence: MFRP NM_031433.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001498
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.401
• Publications: 16 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 11-119342593-C-T is Benign according to our data. Variant chr11-119342593-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.417 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFRP	NM_031433.4	MANE Select	c.1387+3G>A		splice_region intron	N/A	NP_113621.1
	C1QTNF5	NM_015645.5		c.-1250+3G>A		splice_region intron	N/A	NP_056460.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFRP	ENST00000619721.6	TSL:1 MANE Select	c.1387+3G>A		splice_region intron	N/A	ENSP00000481824.1
	MFRP	ENST00000360167.4	TSL:2	c.1161+3G>A		splice_region intron	N/A	ENSP00000353291.4
	MFRP	ENST00000449574.7	TSL:5	c.256+3G>A		splice_region intron	N/A	ENSP00000391664.3

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15598 AN: 151934 Hom.: 1431 Cov.: 33

Gnomad AFR AF: 0.0699

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.0989

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0699

Gnomad OTH AF: 0.0840

GnomAD2 exomes AF: 0.164 AC: 39963 AN: 243588 AF XY: 0.171

Gnomad AFR exome AF: 0.0706

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.104 AC: 151905 AN: 1460554 Hom.: 15509 Cov.: 33 AF XY: 0.112 AC XY: 81524 AN XY: 726552

African (AFR) AF: 0.0639 AC: 2140 AN: 33478

American (AMR) AF: 0.208 AC: 9263 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 1175 AN: 26104

East Asian (EAS) AF: 0.401 AC: 15915 AN: 39668

South Asian (SAS) AF: 0.408 AC: 35124 AN: 86182

European-Finnish (FIN) AF: 0.0989 AC: 5214 AN: 52726

Middle Eastern (MID) AF: 0.0817 AC: 471 AN: 5768

European-Non Finnish (NFE) AF: 0.0679 AC: 75467 AN: 1111742

Other (OTH) AF: 0.118 AC: 7136 AN: 60326

GnomAD4 genome AF: 0.103 AC: 15599 AN: 152052 Hom.: 1434 Cov.: 33 AF XY: 0.113 AC XY: 8421 AN XY: 74340

African (AFR) AF: 0.0698 AC: 2895 AN: 41480

American (AMR) AF: 0.151 AC: 2305 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 160 AN: 3470

East Asian (EAS) AF: 0.419 AC: 2153 AN: 5144

South Asian (SAS) AF: 0.432 AC: 2080 AN: 4814

European-Finnish (FIN) AF: 0.0989 AC: 1049 AN: 10608

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0699 AC: 4747 AN: 67938

Other (OTH) AF: 0.0874 AC: 184 AN: 2106

Alfa AF: 0.0803 Hom.: 1438

Bravo AF: 0.0991

Asia WGS AF: 0.404 AC: 1403 AN: 3478

EpiCase AF: 0.0689

EpiControl AF: 0.0674

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	Isolated microphthalmia 6 (1)
-	-	1	not specified (1)
-	-	1	Retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		0.40
PromoterAI		0.041	Neutral
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs11217241; hg19: chr11-119213303; COSMIC: COSV64128054; COSMIC: COSV64128054;