NM_018557.3:c.13069G>A

Variant names:

• chr2-140274497-C-T
• rs1422402905
• NM_018557.3:c.13069G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_018557.3(LRP1B):​c.13069G>A​(p.Glu4357Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,460,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

LRP1B (HGNC:6693): (LDL receptor related protein 1B) This gene encodes a member of the low density lipoprotein (LDL) receptor family. These receptors play a wide variety of roles in normal cell function and development due to their interactions with multiple ligands. Disruption of this gene has been reported in several types of cancer. [provided by RefSeq, Jun 2016]

ENSG00000300471 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018557.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1B	NM_018557.3	MANE Select	c.13069G>A	p.Glu4357Lys	missense	Exon 85 of 91	NP_061027.2	Q9NZR2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP1B	ENST00000389484.8	TSL:1 MANE Select	c.13069G>A	p.Glu4357Lys	missense	Exon 85 of 91	ENSP00000374135.3	Q9NZR2
	LRP1B	ENST00000437977.5	TSL:5	c.1762G>A	p.Glu588Lys	missense	Exon 12 of 17	ENSP00000415052.1	H0Y7T7
	LRP1B	ENST00000442974.1	TSL:5	c.262G>A	p.Glu88Lys	missense	Exon 2 of 7	ENSP00000393859.1	H7C0A8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250958 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460684 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726666

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111192

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000480 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.73	P
Vest4		0.92
MutPred		0.46		Gain of methylation at E4357 (P = 0.0028)
MVP		0.78
MPC		0.34
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.84
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1422402905; hg19: chr2-141032066;