NM_002334.4:c.1695G>A

Variant names:

• chr11-46892975-C-T
• rs61741501
• NM_002334.4:c.1695G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002334.4(LRP4):​c.1695G>A​(p.Glu565Glu) 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:4
• Conservation: PhyloP100: 0.215
• Publications: 0 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 Gene-Disease associations (from GenCC):

• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• congenital myasthenic syndrome 17

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sclerosteosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sclerosteosis 2

  Inheritance: SD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 304883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1695G>A	p.Glu565Glu	splice_region synonymous	Exon 13 of 38	NP_002325.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP4	ENST00000378623.6	TSL:1 MANE Select	c.1695G>A	p.Glu565Glu	splice_region synonymous	Exon 13 of 38	ENSP00000367888.1

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

GnomAD2 exomes AF: 0.0137 AC: 3430 AN: 250412 AF XY: 0.00991

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 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

African (AFR) AF: 0.180 AC: 6012 AN: 33446

American (AMR) AF: 0.0115 AC: 512 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00660 AC: 34 AN: 5152

European-Non Finnish (NFE) AF: 0.000183 AC: 203 AN: 1111902

Other (OTH) AF: 0.0125 AC: 752 AN: 60316

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

African (AFR) AF: 0.177 AC: 7366 AN: 41526

American (AMR) AF: 0.0206 AC: 316 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68038

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0251 Hom.: 212

Bravo AF: 0.0596

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000475

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.29
CADD	Benign	9.5
DANN	Benign	0.82
PhyloP100		0.21
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61741501; hg19: chr11-46914526;