11-46900321-C-G

Position:

• chr11-46900321-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_002334.4(LRP4):​c.257G>C​(p.Arg86Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP4	NM_002334.4	c.257G>C	p.Arg86Pro	missense_variant	3/38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2	c.257G>C	p.Arg86Pro	missense_variant	3/39		XP_016873223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6	c.257G>C	p.Arg86Pro	missense_variant	3/38	1	NM_002334.4	ENSP00000367888.1
LRP4	ENST00000534404.1	c.110G>C	p.Arg37Pro	missense_variant	2/4	5		ENSP00000434763.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251468 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.2	L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.78
Sift	Benign	0.17	T;T
Sift4G	Benign	0.24	T;.
Polyphen		0.99	D;.
Vest4		0.88
MutPred		0.68		Gain of catalytic residue at R86 (P = 0.0718);.;
MVP		0.92
MPC		0.86
ClinPred		0.66	D
GERP RS		5.6
Varity_R		0.67
gMVP		0.90

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: rs138239756; hg19: chr11-46921872;