11-119344336-C-T

Variant names:

• chr11-119344336-C-T
• rs35885438
• NM_031433.4:c.954G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_031433.4(MFRP):​c.954G>A​(p.Leu318Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,613,670 control chromosomes in the GnomAD database, including 2,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (191 hom., cov: 31)
  • Exomes 𝑓: 0.051 (2451 hom.)
• Consequence: MFRP NM_031433.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0520
• Publications: 12 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-119344336-C-T is Benign according to our data. Variant chr11-119344336-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.116 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.954G>A	p.Leu318Leu	synonymous	Exon 8 of 15	NP_113621.1
	C1QTNF5	NM_015645.5		c.-1683G>A		5_prime_UTR	Exon 8 of 15	NP_056460.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFRP	ENST00000619721.6	TSL:1 MANE Select	c.954G>A	p.Leu318Leu	synonymous	Exon 8 of 15	ENSP00000481824.1
	MFRP	ENST00000360167.4	TSL:2	c.898+296G>A		intron	N/A	ENSP00000353291.4

Frequencies

GnomAD3 genomes AF: 0.0440 AC: 6682 AN: 151934 Hom.: 191 Cov.: 31

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.0376

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0979

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0482

Gnomad OTH AF: 0.0450

GnomAD2 exomes AF: 0.0547 AC: 13585 AN: 248470 AF XY: 0.0601

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0589

Gnomad EAS exome AF: 0.0398

Gnomad FIN exome AF: 0.0922

Gnomad NFE exome AF: 0.0472

Gnomad OTH exome AF: 0.0563

GnomAD4 exome AF: 0.0514 AC: 75090 AN: 1461618 Hom.: 2451 Cov.: 33 AF XY: 0.0539 AC XY: 39187 AN XY: 727114

African (AFR) AF: 0.0209 AC: 700 AN: 33478

American (AMR) AF: 0.0156 AC: 697 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0566 AC: 1480 AN: 26132

East Asian (EAS) AF: 0.0364 AC: 1445 AN: 39700

South Asian (SAS) AF: 0.125 AC: 10773 AN: 86236

European-Finnish (FIN) AF: 0.0875 AC: 4670 AN: 53388

Middle Eastern (MID) AF: 0.0645 AC: 372 AN: 5768

European-Non Finnish (NFE) AF: 0.0465 AC: 51684 AN: 1111810

Other (OTH) AF: 0.0541 AC: 3269 AN: 60386

GnomAD4 genome AF: 0.0439 AC: 6680 AN: 152052 Hom.: 191 Cov.: 31 AF XY: 0.0481 AC XY: 3575 AN XY: 74286

African (AFR) AF: 0.0227 AC: 943 AN: 41466

American (AMR) AF: 0.0204 AC: 311 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3472

East Asian (EAS) AF: 0.0373 AC: 192 AN: 5150

South Asian (SAS) AF: 0.124 AC: 598 AN: 4818

European-Finnish (FIN) AF: 0.0979 AC: 1033 AN: 10552

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0482 AC: 3276 AN: 67998

Other (OTH) AF: 0.0473 AC: 100 AN: 2112

Alfa AF: 0.0436 Hom.: 275

Bravo AF: 0.0339

Asia WGS AF: 0.0890 AC: 309 AN: 3478

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	Retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.0
DANN	Benign	0.86
PhyloP100		0.052
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35885438; hg19: chr11-119215046; COSMIC: COSV64128598; COSMIC: COSV64128598;