chr2-140238174-C-A

Variant names:

• chr2-140238174-C-A
• rs904045513
• NM_018557.3:c.13538G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018557.3(LRP1B):​c.13538G>T​(p.Gly4513Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24045664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1B	NM_018557.3	c.13538G>T	p.Gly4513Val	missense_variant	Exon 89 of 91	ENST00000389484.8	NP_061027.2
LRP1B	XM_017004341.2	c.13148G>T	p.Gly4383Val	missense_variant	Exon 89 of 91		XP_016859830.1
LRP1B	XM_017004342.1	c.8390G>T	p.Gly2797Val	missense_variant	Exon 60 of 62		XP_016859831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1B	ENST00000389484.8	c.13538G>T	p.Gly4513Val	missense_variant	Exon 89 of 91	1	NM_018557.3	ENSP00000374135.3
LRP1B	ENST00000437977.5	c.2231G>T	p.Gly744Val	missense_variant	Exon 16 of 17	5		ENSP00000415052.1
LRP1B	ENST00000442974.1	c.*8G>T		downstream_gene_variant		5		ENSP00000393859.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452746 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13538G>T (p.G4513V) alteration is located in exon 89 (coding exon 89) of the LRP1B gene. This alteration results from a G to T substitution at nucleotide position 13538, causing the glycine (G) at amino acid position 4513 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.15
Sift	Uncertain	0.020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.18	B
Vest4		0.29
MutPred		0.59		Gain of sheet (P = 0.0221);
MVP		0.24
MPC		0.25
ClinPred		0.70	D
GERP RS		4.8
Varity_R		0.10
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs904045513; hg19: chr2-140995743;