chr4-185375684-C-T

Variant names:

• chr4-185375684-C-T
• rs886384021
• NM_001377440.1:c.259G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377440.1(LRP2BP):​c.259G>A​(p.Glu87Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E87Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRP2BP NM_001377440.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16
• Publications: 0 publications found

Genes affected

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

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24587455).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377440.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2BP	NM_001377440.1	MANE Select	c.259G>A	p.Glu87Lys	missense	Exon 4 of 9	NP_001364369.1	Q9P2M1-1
	LRP2BP	NM_001385601.1		c.259G>A	p.Glu87Lys	missense	Exon 4 of 9	NP_001372530.1	Q9P2M1-1
	LRP2BP	NM_018409.4		c.259G>A	p.Glu87Lys	missense	Exon 3 of 8	NP_060879.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2BP	ENST00000505916.6	TSL:2 MANE Select	c.259G>A	p.Glu87Lys	missense	Exon 4 of 9	ENSP00000426203.1	Q9P2M1-1
	LRP2BP	ENST00000328559.11	TSL:1	c.259G>A	p.Glu87Lys	missense	Exon 3 of 8	ENSP00000332681.7	Q9P2M1-1
	LRP2BP	ENST00000510776.5	TSL:1	c.181G>A	p.Glu61Lys	missense	Exon 2 of 7	ENSP00000424610.1	G5E9Z9

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150912 Hom.: 0 Cov.: 28

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251042 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460904 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726750

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111410

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150912 Hom.: 0 Cov.: 28 AF XY: 0.0000136 AC XY: 1 AN XY: 73610

African (AFR) AF: 0.00 AC: 0 AN: 40964

American (AMR) AF: 0.00 AC: 0 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67798

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.084
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Benign	0.16	T
Sift4G	Benign	0.20	T
Polyphen		0.64	P
Vest4		0.35
MutPred		0.51		Gain of ubiquitination at E87 (P = 0.0325)
MVP		0.73
MPC		0.29
ClinPred		0.41	T
GERP RS		5.1
Varity_R		0.20
gMVP		0.21
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs886384021; hg19: chr4-186296838;