chr2-140274437-C-A

Position:

• chr2-140274437-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018557.3(LRP1B):​c.13129G>T​(p.Asp4377Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.13129G>T	p.Asp4377Tyr	missense_variant	85/91	ENST00000389484.8
LRP1B	XM_017004341.2	c.12739G>T	p.Asp4247Tyr	missense_variant	85/91
LRP1B	XM_017004342.1	c.7981G>T	p.Asp2661Tyr	missense_variant	56/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.13129G>T	p.Asp4377Tyr	missense_variant	85/91	1	NM_018557.3	P1
LRP1B	ENST00000437977.5	c.1825G>T	p.Asp609Tyr	missense_variant	12/17	5
LRP1B	ENST00000442974.1	c.325G>T	p.Asp109Tyr	missense_variant	2/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.13129G>T (p.D4377Y) alteration is located in exon 85 (coding exon 85) of the LRP1B gene. This alteration results from a G to T substitution at nucleotide position 13129, causing the aspartic acid (D) at amino acid position 4377 to be replaced by a tyrosine (Y). 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	0.16
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.66		Gain of methylation at K4373 (P = 0.0461);
MVP		0.53
MPC		0.73
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.29
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs150457308; hg19: chr2-141032006; COSMIC: COSV67191226;