Genetic Variant LRP2BP:p.His39Tyr (chr4-185377010-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001377440.1(LRP2BP):c.115C>T(p.His39Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,364 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LRP2BP
NM_001377440.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.68

Variant links:

Genes affected

LRP2BP (HGNC:25434): (LRP2 binding protein) Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LRP2BP links:

LRP2BP-AS1 (HGNC:):

LRP2BP-AS1 links:

SNX25 (HGNC:21883): (sorting nexin 25) Predicted to enable type I transforming growth factor beta receptor binding activity. Involved in negative regulation of pathway-restricted SMAD protein phosphorylation; negative regulation of transforming growth factor beta receptor signaling pathway; and receptor catabolic process. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

SNX25 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2BP	NM_001377440.1 link	c.115C>T	p.His39Tyr	missense_variant	Exon 3 of 9	ENST00000505916.6	NP_001364369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP2BP	ENST00000505916.6 link	c.115C>T	p.His39Tyr	missense_variant	Exon 3 of 9	2	NM_001377440.1	ENSP00000426203.1		Q9P2M1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455364

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724520

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

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

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115C>T (p.H39Y) alteration is located in exon 2 (coding exon 2) of the LRP2BP gene. This alteration results from a C to T substitution at nucleotide position 115, causing the histidine (H) at amino acid position 39 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

0.19

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.56

.;T;T;T

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.50

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.3

M;.;M;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.012

D;D;D;D

Sift4G

Uncertain

0.041

D;D;D;.

Polyphen

1.0

D;D;D;.

Vest4

0.56

MutPred

0.33

Gain of glycosylation at Y37 (P = 0.0308);.;Gain of glycosylation at Y37 (P = 0.0308);Gain of glycosylation at Y37 (P = 0.0308);

MVP

0.62

MPC

0.80

ClinPred

0.93

GERP RS

5.9

Varity_R

0.12

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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