chr4-185372940-C-T

Variant names:

• chr4-185372940-C-T
• rs748366572
• NM_001377440.1:c.719G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001377440.1(LRP2BP):​c.719G>A​(p.Arg240His) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R240C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LRP2BP NM_001377440.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

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.719G>A	p.Arg240His	missense	Exon 7 of 9	NP_001364369.1	Q9P2M1-1
	LRP2BP	NM_001385601.1		c.719G>A	p.Arg240His	missense	Exon 7 of 9	NP_001372530.1	Q9P2M1-1
	LRP2BP	NM_018409.4		c.719G>A	p.Arg240His	missense	Exon 6 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.719G>A	p.Arg240His	missense	Exon 7 of 9	ENSP00000426203.1	Q9P2M1-1
	LRP2BP	ENST00000328559.11	TSL:1	c.719G>A	p.Arg240His	missense	Exon 6 of 8	ENSP00000332681.7	Q9P2M1-1
	LRP2BP	ENST00000510776.5	TSL:1	c.641G>A	p.Arg214His	missense	Exon 5 of 7	ENSP00000424610.1	G5E9Z9

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251450 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461622 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727070

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111774

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

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	0.21
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.61		Gain of glycosylation at Y244 (P = 0.0492)
MVP		0.77
MPC		0.86
ClinPred		0.88	D
GERP RS		6.1
Varity_R		0.19
gMVP		0.51
Mutation Taster		=76/24	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: rs748366572; hg19: chr4-186294094;