Variant 4-185367245-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001377440.1(LRP2BP):c.979G>A(p.Ala327Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000186 in 1,609,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRP2BP
NM_001377440.1 missense, splice_region

Scores

Splicing: ADA: 0.9995

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44

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:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP2BP	NM_001377440.1 link	c.979G>A	p.Ala327Thr	missense_variant, splice_region_variant	Exon 9 of 9	ENST00000505916.6	NP_001364369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRP2BP	ENST00000505916.6 link	c.979G>A	p.Ala327Thr	missense_variant, splice_region_variant	Exon 9 of 9	2	NM_001377440.1	ENSP00000426203.1	Q9P2M1-1
LRP2BP	ENST00000328559.11 link	c.979G>A	p.Ala327Thr	missense_variant, splice_region_variant	Exon 8 of 8	1		ENSP00000332681.7	Q9P2M1-1
LRP2BP	ENST00000510776.5 link	c.901G>A	p.Ala301Thr	missense_variant, splice_region_variant	Exon 7 of 7	1		ENSP00000424610.1	G5E9Z9
SNX25	ENST00000504959.5 link	n.*1005-2505C>T		intron_variant	Intron 11 of 11	2		ENSP00000424826.1	H0Y9R5

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457636

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725134

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151440

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73902

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

The c.979G>A (p.A327T) alteration is located in exon 8 (coding exon 8) of the LRP2BP gene. This alteration results from a G to A substitution at nucleotide position 979, causing the alanine (A) at amino acid position 327 to be replaced by a threonine (T). 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

Uncertain

0.43

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;.;T

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

.;T;T

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.3

M;.;M

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.85

MVP

0.86

MPC

0.51

ClinPred

0.99

GERP RS

5.7

Varity_R

0.52

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over