11-46875564-G-T

Position:

• chr11-46875564-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_002334.4(LRP4):​c.3817C>A​(p.Arg1273=) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,614,078 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (22 hom.)
• Consequence: LRP4 NM_002334.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 8.13

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 11-46875564-G-T is Benign according to our data. Variant chr11-46875564-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211405.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0036 (548/152206) while in subpopulation NFE AF= 0.00503 (342/68008). AF 95% confidence interval is 0.00459. There are 1 homozygotes in gnomad4. There are 321 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 22 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP4	NM_002334.4	c.3817C>A	p.Arg1273=	synonymous_variant	27/38	ENST00000378623.6	NP_002325.2
LRP4	XM_017017734.2	c.3817C>A	p.Arg1273=	synonymous_variant	27/39		XP_016873223.1
LRP4	XM_011520103.3	c.3013C>A	p.Arg1005=	synonymous_variant	21/32		XP_011518405.1
LRP4	XM_011520104.3	c.1582C>A	p.Arg528=	synonymous_variant	12/23		XP_011518406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP4	ENST00000378623.6	c.3817C>A	p.Arg1273=	synonymous_variant	27/38	1	NM_002334.4	ENSP00000367888	P1

Frequencies

GnomAD3 genomes AF: 0.00360 AC: 548 AN: 152088 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00503

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00403 AC: 1012 AN: 251250 Hom.: 8 AF XY: 0.00415 AC XY: 563 AN XY: 135778

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.00553

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00291 AC: 4251 AN: 1461872 Hom.: 22 Cov.: 35 AF XY: 0.00301 AC XY: 2188 AN XY: 727236

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.00292

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00360 AC: 548 AN: 152206 Hom.: 1 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74430

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.00503

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00427 Hom.: 4

Bravo AF: 0.00214

EpiCase AF: 0.00376

EpiControl AF: 0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	LRP4: BP4, BS2 -

Cenani-Lenz syndactyly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 13, 2017

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.0
DANN	Benign	0.79

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: rs61746928; hg19: chr11-46897115;