rs369307795

Positions:

• chr11-46896940-C-A
• chr11-46896940-C-T

Variant summary

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

The NM_002334.4(LRP4):​c.851G>T​(p.Arg284Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17

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.851G>T	p.Arg284Leu	missense_variant	8/38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2	c.851G>T	p.Arg284Leu	missense_variant	8/39		XP_016873223.1
LRP4	XM_011520103.3	c.47G>T	p.Arg16Leu	missense_variant	2/32		XP_011518405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6	c.851G>T	p.Arg284Leu	missense_variant	8/38	1	NM_002334.4	ENSP00000367888.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	-0.17	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.55
Sift	Benign	0.41	T
Sift4G	Benign	0.72	T
Polyphen		0.024	B
Vest4		0.75
MutPred		0.62		Loss of MoRF binding (P = 0.0546);
MVP		0.66
MPC		0.77
ClinPred		0.34	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369307795; hg19: chr11-46918491;