Genetic Variant NM_018557.3:c.12977A>G (chr2-140274589-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018557.3(LRP1B):c.12977A>G(p.His4326Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LRP1B
NM_018557.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.25

Variant links:

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]

LRP1B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38169253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1B	NM_018557.3 link	c.12977A>G	p.His4326Arg	missense_variant	Exon 85 of 91	ENST00000389484.8	NP_061027.2	Q9NZR2
LRP1B	XM_017004341.2 link	c.12587A>G	p.His4196Arg	missense_variant	Exon 85 of 91		XP_016859830.1
LRP1B	XM_017004342.1 link	c.7829A>G	p.His2610Arg	missense_variant	Exon 56 of 62		XP_016859831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP1B	ENST00000389484.8 link	c.12977A>G	p.His4326Arg	missense_variant	Exon 85 of 91	1	NM_018557.3	ENSP00000374135.3	Q9NZR2
LRP1B	ENST00000437977.5 link	c.1670A>G	p.His557Arg	missense_variant	Exon 12 of 17	5		ENSP00000415052.1	H0Y7T7
LRP1B	ENST00000442974.1 link	c.170A>G	p.His57Arg	missense_variant	Exon 2 of 7	5		ENSP00000393859.1	H7C0A8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725082

show subpopulations

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.12977A>G (p.H4326R) alteration is located in exon 85 (coding exon 85) of the LRP1B gene. This alteration results from a A to G substitution at nucleotide position 12977, causing the histidine (H) at amino acid position 4326 to be replaced by an arginine (R). 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

0.14

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.071

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.72

M_CAP

Benign

0.033

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.76

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.64

REVEL

Uncertain

0.54

Sift

Benign

0.56

Sift4G

Benign

0.26

Polyphen

0.98

Vest4

0.33

MutPred

0.59

Loss of catalytic residue at C4325 (P = 0.1851);

MVP

0.40

MPC

0.33

ClinPred

0.56

GERP RS

5.4

Varity_R

0.11

gMVP

0.43

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over