rs150681693

Positions:

• chr11-46875085-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The NM_002334.4(LRP4):​c.3944C>T​(p.Ser1315Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,613,310 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1315S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (6 hom.)
• Consequence: LRP4 NM_002334.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.974

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP4
• BP4: Computational evidence support a benign effect (MetaRNN=0.021962434).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000453 (69/152294) while in subpopulation NFE AF= 0.000794 (54/68022). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP4	NM_002334.4	c.3944C>T	p.Ser1315Leu	missense_variant	28/38	ENST00000378623.6
LRP4	XM_017017734.2	c.3944C>T	p.Ser1315Leu	missense_variant	28/39
LRP4	XM_011520103.3	c.3140C>T	p.Ser1047Leu	missense_variant	22/32
LRP4	XM_011520104.3	c.1709C>T	p.Ser570Leu	missense_variant	13/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP4	ENST00000378623.6	c.3944C>T	p.Ser1315Leu	missense_variant	28/38	1	NM_002334.4	P1

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000451 AC: 113 AN: 250556 Hom.: 1 AF XY: 0.000465 AC XY: 63 AN XY: 135510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000890

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000801 AC: 1170 AN: 1461016 Hom.: 6 Cov.: 32 AF XY: 0.000780 AC XY: 567 AN XY: 726854

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000567

Gnomad4 NFE exome AF: 0.000978

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74476

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000759 Hom.: 0

Bravo AF: 0.000487

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 12, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 14, 2017

- -

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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.3944C>T (p.S1315L) alteration is located in exon 28 (coding exon 28) of the LRP4 gene. This alteration results from a C to T substitution at nucleotide position 3944, causing the serine (S) at amino acid position 1315 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.4
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.015	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.22
Sift	Benign	0.30	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.21
MVP		0.56
MPC		0.48
ClinPred		0.022	T
GERP RS		1.8
Varity_R		0.055
gMVP		0.064

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: rs150681693; hg19: chr11-46896636; COSMIC: COSV66134008; COSMIC: COSV66134008;