rs9640

Variant names:

• chr11-119339269-T-A
• rs9640
• NM_031433.4:c.*1690A>T

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.*1690A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,558,354 control chromosomes in the GnomAD database, including 16,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2306 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14138 hom.)
• Consequence: MFRP NM_031433.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.317
• 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):

• 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 (BayesDel_noAF=-0.75).
• BP6: Variant 11-119339269-T-A is Benign according to our data. Variant chr11-119339269-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 302922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFRP	NM_031433.4	c.*1690A>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_001278431.2	c.*62A>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000528368.3	NP_001265360.1
C1QTNF5	NM_015645.5	c.*62A>T		3_prime_UTR_variant	Exon 15 of 15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6	c.*1690A>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_031433.4	ENSP00000481824.1
C1QTNF5	ENST00000528368.3	c.*62A>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_001278431.2	ENSP00000431140.1
C1QTNF5	ENST00000530681.2	c.*62A>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000456533.2
C1QTNF5	ENST00000525657.2	n.*101A>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24673 AN: 151884 Hom.: 2303 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.0577

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.161

GnomAD4 exome AF: 0.137 AC: 192260 AN: 1406352 Hom.: 14138 Cov.: 28 AF XY: 0.134 AC XY: 93052 AN XY: 695350

African (AFR) AF: 0.253 AC: 8031 AN: 31716

American (AMR) AF: 0.0780 AC: 3028 AN: 38844

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 2278 AN: 22998

East Asian (EAS) AF: 0.0495 AC: 1941 AN: 39190

South Asian (SAS) AF: 0.0599 AC: 4789 AN: 79908

European-Finnish (FIN) AF: 0.191 AC: 9769 AN: 51244

Middle Eastern (MID) AF: 0.155 AC: 850 AN: 5478

European-Non Finnish (NFE) AF: 0.143 AC: 153798 AN: 1079078

Other (OTH) AF: 0.134 AC: 7776 AN: 57896

GnomAD4 genome AF: 0.163 AC: 24702 AN: 152002 Hom.: 2306 Cov.: 32 AF XY: 0.162 AC XY: 12028 AN XY: 74318

African (AFR) AF: 0.242 AC: 10047 AN: 41448

American (AMR) AF: 0.120 AC: 1829 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 360 AN: 3470

East Asian (EAS) AF: 0.0352 AC: 181 AN: 5136

South Asian (SAS) AF: 0.0580 AC: 279 AN: 4812

European-Finnish (FIN) AF: 0.197 AC: 2085 AN: 10592

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9407 AN: 67948

Other (OTH) AF: 0.159 AC: 335 AN: 2106

Alfa AF: 0.149 Hom.: 257

Bravo AF: 0.162

Asia WGS AF: 0.0590 AC: 205 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated microphthalmia 6 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal degeneration Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.7
DANN	Benign	0.73
PhyloP100		-0.32
Mutation Taster		=100/0	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: rs9640; hg19: chr11-119209979;