chr11-46894763-G-A

Position:

• chr11-46894763-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000378623.6(LRP4):​c.1366C>T​(p.His456Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H456H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRP4 ENST00000378623.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

LRP4 (HGNC:6696): (LDL receptor related protein 4) This gene encodes a member of the low-density lipoprotein receptor-related protein family. The encoded protein may be a regulator of Wnt signaling. Mutations in this gene are associated with Cenani-Lenz syndrome. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LRP4. . Gene score misZ 3.0632 (greater than the threshold 3.09). Trascript score misZ 5.2056 (greater than threshold 3.09). GenCC has associacion of gene with postsynaptic congenital myasthenic syndrome, sclerosteosis, Cenani-Lenz syndactyly syndrome, sclerosteosis 2, congenital myasthenic syndrome 17.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP4	NM_002334.4	c.1366C>T	p.His456Tyr	missense_variant	12/38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2	c.1366C>T	p.His456Tyr	missense_variant	12/39		XP_016873223.1
LRP4	XM_011520103.3	c.562C>T	p.His188Tyr	missense_variant	6/32		XP_011518405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6	c.1366C>T	p.His456Tyr	missense_variant	12/38	1	NM_002334.4	ENSP00000367888	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with LRP4-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with tyrosine at codon 456 of the LRP4 protein (p.His456Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.017	D
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.61
Sift	Benign	0.29	T
Sift4G	Benign	0.24	T
Polyphen		0.29	B
Vest4		0.82
MutPred		0.57		Gain of catalytic residue at Q452 (P = 0.0738);
MVP		0.78
MPC		0.79
ClinPred		0.57	D
GERP RS		5.5
Varity_R		0.25
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555174047; hg19: chr11-46916314;