11-119345521-A-T

Variant names:

• chr11-119345521-A-T
• rs2510143
• NM_031433.4:c.540T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031433.4(MFRP):​c.540T>A​(p.His180Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H180H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFRP NM_031433.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.25
• Publications: 31 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040366143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFRP	NM_031433.4	c.540T>A	p.His180Gln	missense_variant	Exon 5 of 15	ENST00000619721.6	NP_113621.1
C1QTNF5	NM_015645.5	c.-2097T>A		5_prime_UTR_variant	Exon 5 of 15		NP_056460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFRP	ENST00000619721.6	c.540T>A	p.His180Gln	missense_variant	Exon 5 of 15	1	NM_031433.4	ENSP00000481824.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.019
DANN	Benign	0.68
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.23	N;N
PhyloP100		-2.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.16	.;N
REVEL	Benign	0.034
Sift	Benign	0.93	.;T
Sift4G	Benign	0.87	T;T
Polyphen		0.0020	B;.
Vest4		0.13
MutPred		0.53		Gain of catalytic residue at H180 (P = 0.0918);Gain of catalytic residue at H180 (P = 0.0918);
MVP		0.048
ClinPred		0.053	T
GERP RS		-8.0
Varity_R		0.032
gMVP		0.42
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2510143; hg19: chr11-119216231;