2-140274452-T-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_018557.3(LRP1B):c.13114A>T(p.Asn4372Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,612,564 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (46 hom.)
• Consequence: LRP1B NM_018557.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.11

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRP1B
• BP4: Computational evidence support a benign effect (MetaRNN=0.015412033).
• BP6: Variant 2-140274452-T-A is Benign according to our data. Variant chr2-140274452-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 772849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 683 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRP1B	NM_018557.3	c.13114A>T	p.Asn4372Tyr	missense_variant	85/91	ENST00000389484.8
LRP1B	XM_017004341.2	c.12724A>T	p.Asn4242Tyr	missense_variant	85/91
LRP1B	XM_017004342.1	c.7966A>T	p.Asn2656Tyr	missense_variant	56/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRP1B	ENST00000389484.8	c.13114A>T	p.Asn4372Tyr	missense_variant	85/91	1	NM_018557.3	P1
LRP1B	ENST00000437977.5	c.1810A>T	p.Asn604Tyr	missense_variant	12/17	5
LRP1B	ENST00000442974.1	c.310A>T	p.Asn104Tyr	missense_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 683 AN: 152046 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00492

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00668

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00563 AC: 1412 AN: 250716 Hom.: 9 AF XY: 0.00570 AC XY: 773 AN XY: 135536

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.00676

Gnomad NFE exome AF: 0.00815

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00609 AC: 8893 AN: 1460400 Hom.: 46 Cov.: 30 AF XY: 0.00598 AC XY: 4344 AN XY: 726518

Gnomad4 AFR exome AF: 0.000719

Gnomad4 AMR exome AF: 0.00412

Gnomad4 ASJ exome AF: 0.00514

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00389

Gnomad4 FIN exome AF: 0.00554

Gnomad4 NFE exome AF: 0.00673

Gnomad4 OTH exome AF: 0.00665

GnomAD4 genome AF: 0.00449 AC: 683 AN: 152164 Hom.: 2 Cov.: 33 AF XY: 0.00455 AC XY: 338 AN XY: 74360

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00492

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.00668

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00609 Hom.: 1

Bravo AF: 0.00461

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00628 AC: 762

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	LRP1B: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

LRP1B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.081
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.69	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.14	B
Vest4		0.74
MVP		0.58
MPC		0.61
ClinPred		0.023	T
GERP RS		2.9
Varity_R		0.18
gMVP		0.85

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: rs149644677; hg19: chr2-141032021; COSMIC: COSV67186330;