NM_002334.4:c.5010G>A

Variant names:

• chr11-46868056-C-T
• rs111426027
• NM_002334.4:c.5010G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002334.4(LRP4):​c.5010G>A​(p.Val1670Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,108 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (152 hom.)
• Consequence: LRP4 NM_002334.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.250
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 11-46868056-C-T is Benign according to our data. Variant chr11-46868056-C-T is described in ClinVar as Benign. ClinVar VariationId is 467791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.25 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00929 (1415/152234) while in subpopulation NFE AF = 0.014 (955/68018). AF 95% confidence interval is 0.0133. There are 13 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR,SD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	NM_002334.4	MANE Select	c.5010G>A	p.Val1670Val	synonymous	Exon 34 of 38	NP_002325.2
	LRP4-AS1	NR_038909.1		n.198-5018C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.5010G>A	p.Val1670Val	synonymous	Exon 34 of 38	ENSP00000367888.1
	LRP4-AS1	ENST00000502049.4	TSL:2	n.197-5018C>T		intron	N/A
	LRP4-AS1	ENST00000531719.5	TSL:4	n.292-5018C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1414 AN: 152116 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00871

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0112 AC: 2828 AN: 251486 AF XY: 0.0118

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00744

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0125 AC: 18267 AN: 1461874 Hom.: 152 Cov.: 32 AF XY: 0.0127 AC XY: 9263 AN XY: 727238

African (AFR) AF: 0.00182 AC: 61 AN: 33480

American (AMR) AF: 0.00695 AC: 311 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 417 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0155 AC: 1334 AN: 86258

European-Finnish (FIN) AF: 0.00749 AC: 400 AN: 53420

Middle Eastern (MID) AF: 0.0203 AC: 117 AN: 5764

European-Non Finnish (NFE) AF: 0.0134 AC: 14903 AN: 1111996

Other (OTH) AF: 0.0120 AC: 724 AN: 60396

GnomAD4 genome AF: 0.00929 AC: 1415 AN: 152234 Hom.: 13 Cov.: 32 AF XY: 0.00907 AC XY: 675 AN XY: 74444

African (AFR) AF: 0.00197 AC: 82 AN: 41534

American (AMR) AF: 0.00870 AC: 133 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0128 AC: 62 AN: 4826

European-Finnish (FIN) AF: 0.00877 AC: 93 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 955 AN: 68018

Other (OTH) AF: 0.0128 AC: 27 AN: 2110

Alfa AF: 0.0127 Hom.: 25

Bravo AF: 0.00861

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0156

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cenani-Lenz syndactyly syndrome (1)
-	-	1	Cenani-Lenz syndactyly syndrome;C3280402:Sclerosteosis 2;C4225377:Congenital myasthenic syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism

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: rs111426027; hg19: chr11-46889607;