rs61741501

chr11-46892975-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002334.4(LRP4):c.1695G>A(p.Glu565=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00954 in 1,613,154 control chromosomes in the GnomAD database, including 1,274 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (670 hom., cov: 31)
  • Exomes 𝑓: 0.0052 (604 hom.)
• Consequence: LRP4 NM_002334.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00004263
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.215

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 11-46892975-C-T is Benign according to our data. Variant chr11-46892975-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 304883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-46892975-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.215 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP4	NM_002334.4	c.1695G>A	p.Glu565=	splice_region_variant, synonymous_variant	13/38	ENST00000378623.6
LRP4	XM_017017734.2	c.1695G>A	p.Glu565=	splice_region_variant, synonymous_variant	13/39
LRP4	XM_011520103.3	c.891G>A	p.Glu297=	splice_region_variant, synonymous_variant	7/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6	c.1695G>A	p.Glu565=	splice_region_variant, synonymous_variant	13/38	1	NM_002334.4	P1

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7787 AN: 152176 Hom.: 670 Cov.: 31

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0137 AC: 3430 AN: 250412 Hom.: 286 AF XY: 0.00991 AC XY: 1342 AN XY: 135406

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00520 AC: 7591 AN: 1460860 Hom.: 604 Cov.: 30 AF XY: 0.00444 AC XY: 3228 AN XY: 726686

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0512 AC: 7804 AN: 152294 Hom.: 670 Cov.: 31 AF XY: 0.0491 AC XY: 3658 AN XY: 74472

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0218 Hom.: 149

Bravo AF: 0.0596

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000475

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cenani-Lenz syndactyly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	9.5
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.030
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: rs61741501; hg19: chr11-46914526;