11-46868614-C-T

Variant names:

• chr11-46868614-C-T
• rs3816614
• NM_002334.4:c.4937G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002334.4(LRP4):​c.4937G>A​(p.Arg1646Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 1,612,518 control chromosomes in the GnomAD database, including 437,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1646L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.64 (33083 hom., cov: 31)
  • Exomes 𝑓: 0.74 (404028 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.35
• Publications: 50 publications found

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]

LRP4-AS1 (HGNC:44128): (LRP4 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.1250956E-7).
• BP6: Variant 11-46868614-C-T is Benign according to our data. Variant chr11-46868614-C-T is described in ClinVar as Benign. ClinVar VariationId is 304850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002334.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	NM_002334.4	MANE Select	c.4937G>A	p.Arg1646Gln	missense	Exon 33 of 38	NP_002325.2	O75096
	LRP4-AS1	NR_038909.1		n.198-4460C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.4937G>A	p.Arg1646Gln	missense	Exon 33 of 38	ENSP00000367888.1	O75096
	LRP4	ENST00000858258.1		c.4388G>A	p.Arg1463Gln	missense	Exon 30 of 35	ENSP00000528317.1
	LRP4-AS1	ENST00000502049.4	TSL:2	n.197-4460C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97579 AN: 151964 Hom.: 33070 Cov.: 31

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.810

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.683

GnomAD2 exomes AF: 0.679 AC: 170284 AN: 250940 AF XY: 0.694

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.537

Gnomad ASJ exome AF: 0.807

Gnomad EAS exome AF: 0.377

Gnomad FIN exome AF: 0.683

Gnomad NFE exome AF: 0.776

Gnomad OTH exome AF: 0.744

GnomAD4 exome AF: 0.738 AC: 1077370 AN: 1460436 Hom.: 404028 Cov.: 40 AF XY: 0.740 AC XY: 537487 AN XY: 726572

African (AFR) AF: 0.417 AC: 13938 AN: 33440

American (AMR) AF: 0.554 AC: 24762 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 21159 AN: 26132

East Asian (EAS) AF: 0.381 AC: 15136 AN: 39692

South Asian (SAS) AF: 0.729 AC: 62856 AN: 86236

European-Finnish (FIN) AF: 0.692 AC: 36927 AN: 53386

Middle Eastern (MID) AF: 0.748 AC: 4311 AN: 5766

European-Non Finnish (NFE) AF: 0.769 AC: 854215 AN: 1110730

Other (OTH) AF: 0.730 AC: 44066 AN: 60330

GnomAD4 genome AF: 0.642 AC: 97611 AN: 152082 Hom.: 33083 Cov.: 31 AF XY: 0.637 AC XY: 47355 AN XY: 74330

African (AFR) AF: 0.429 AC: 17769 AN: 41460

American (AMR) AF: 0.655 AC: 10005 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 2813 AN: 3472

East Asian (EAS) AF: 0.393 AC: 2028 AN: 5160

South Asian (SAS) AF: 0.725 AC: 3490 AN: 4812

European-Finnish (FIN) AF: 0.674 AC: 7126 AN: 10580

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.765 AC: 52031 AN: 67996

Other (OTH) AF: 0.689 AC: 1458 AN: 2116

Alfa AF: 0.736 Hom.: 121990

Bravo AF: 0.629

TwinsUK AF: 0.780 AC: 2892

ALSPAC AF: 0.759 AC: 2927

ESP6500AA AF: 0.442 AC: 1947

ESP6500EA AF: 0.772 AC: 6634

ExAC AF: 0.684 AC: 83070

Asia WGS AF: 0.620 AC: 2157 AN: 3478

EpiCase AF: 0.776

EpiControl AF: 0.783

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cenani-Lenz syndactyly syndrome (2)
-	-	2	not provided (2)
-	-	1	Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 (1)
-	-	1	Congenital myasthenic syndrome 17 (1)
-	-	1	Sclerosteosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	9.1e-7	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.25
Sift	Benign	0.20	T
Sift4G	Benign	0.57	T
Polyphen		0.0050	B
Vest4		0.055
MPC		0.64
ClinPred		0.0065	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.71
Mutation Taster		=94/6	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: rs3816614; hg19: chr11-46890165; COSMIC: COSV66134158; COSMIC: COSV66134158;