11-119345794-C-T

Variant names:

• chr11-119345794-C-T
• rs3814762
• NM_031433.4:c.406G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015645.5(C1QTNF5):​c.-2231G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,613,314 control chromosomes in the GnomAD database, including 78,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5540 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73308 hom.)
• Consequence: C1QTNF5 NM_015645.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.46
• Publications: 34 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=0.004874885).
• BP6: Variant 11-119345794-C-T is Benign according to our data. Variant chr11-119345794-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015645.5. 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.406G>A	p.Val136Met	missense	Exon 4 of 15	NP_113621.1	Q9BY79-1
	C1QTNF5	NM_015645.5		c.-2231G>A		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_056460.1	Q9BXJ0
	C1QTNF5	NM_015645.5		c.-2231G>A		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.406G>A	p.Val136Met	missense	Exon 4 of 15	ENSP00000481824.1	Q9BY79-1
	MFRP	ENST00000360167.4	TSL:2	c.406G>A	p.Val136Met	missense	Exon 4 of 10	ENSP00000353291.4	Q9BY79-2
	MFRP	ENST00000526059.1	TSL:3	n.564G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37345 AN: 151884 Hom.: 5541 Cov.: 32

Gnomad AFR AF: 0.0890

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.265 AC: 65587 AN: 247454 AF XY: 0.273

Gnomad AFR exome AF: 0.0855

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.311

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.311 AC: 454796 AN: 1461312 Hom.: 73308 Cov.: 65 AF XY: 0.311 AC XY: 225727 AN XY: 726938

African (AFR) AF: 0.0799 AC: 2675 AN: 33480

American (AMR) AF: 0.174 AC: 7767 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8016 AN: 26134

East Asian (EAS) AF: 0.205 AC: 8152 AN: 39698

South Asian (SAS) AF: 0.230 AC: 19837 AN: 86258

European-Finnish (FIN) AF: 0.316 AC: 16742 AN: 52972

Middle Eastern (MID) AF: 0.325 AC: 1875 AN: 5766

European-Non Finnish (NFE) AF: 0.334 AC: 371465 AN: 1111894

Other (OTH) AF: 0.303 AC: 18267 AN: 60386

GnomAD4 genome AF: 0.246 AC: 37336 AN: 152002 Hom.: 5540 Cov.: 32 AF XY: 0.244 AC XY: 18112 AN XY: 74298

African (AFR) AF: 0.0890 AC: 3691 AN: 41492

American (AMR) AF: 0.220 AC: 3367 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1073 AN: 3464

East Asian (EAS) AF: 0.195 AC: 999 AN: 5134

South Asian (SAS) AF: 0.215 AC: 1034 AN: 4812

European-Finnish (FIN) AF: 0.324 AC: 3425 AN: 10562

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22575 AN: 67948

Other (OTH) AF: 0.289 AC: 610 AN: 2112

Alfa AF: 0.289 Hom.: 17206

Bravo AF: 0.233

TwinsUK AF: 0.345 AC: 1280

ALSPAC AF: 0.331 AC: 1276

ESP6500AA AF: 0.0975 AC: 429

ESP6500EA AF: 0.323 AC: 2771

ExAC AF: 0.265 AC: 32153

Asia WGS AF: 0.189 AC: 657 AN: 3478

EpiCase AF: 0.340

EpiControl AF: 0.338

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Isolated microphthalmia 5 (2)
-	-	1	Isolated microphthalmia 6 (1)
-	-	1	not provided (1)
-	-	1	Retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.011
DANN	Benign	0.86
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-2.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.039
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.0080	B
Vest4		0.047
ClinPred		0.00030	T
GERP RS		-3.1
Varity_R		0.023
gMVP		0.26
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs3814762; hg19: chr11-119216504; COSMIC: COSV64128333; COSMIC: COSV64128333;