chr1-53258321-C-T

Position:

• chr1-53258321-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000306052.12(LRP8):​c.2207G>A​(p.Arg736Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000737 in 1,613,604 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (4 hom.)
• Consequence: LRP8 ENST00000306052.12 missense, splice_region
• Scores: Splicing: ADA: 0.3690
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.81

Genes affected

LRP8 (HGNC:6700): (LDL receptor related protein 8) This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

LOC105378728 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061583817).
• BP6: Variant 1-53258321-C-T is Benign according to our data. Variant chr1-53258321-C-T is described in ClinVar as [Benign]. Clinvar id is 711273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 565 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP8	NM_004631.5	c.2207G>A	p.Arg736Gln	missense_variant, splice_region_variant	14/19	ENST00000306052.12	NP_004622.2
LOC105378728	XR_947355.3	n.4349+1840C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12	c.2207G>A	p.Arg736Gln	missense_variant, splice_region_variant	14/19	1	NM_004631.5	ENSP00000303634	A2

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 561 AN: 152212 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00103 AC: 257 AN: 250184 Hom.: 0 AF XY: 0.000799 AC XY: 108 AN XY: 135156

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.000427 AC: 624 AN: 1461274 Hom.: 4 Cov.: 31 AF XY: 0.000376 AC XY: 273 AN XY: 726964

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000738

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00371 AC: 565 AN: 152330 Hom.: 5 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74480

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000577 Hom.: 0

Bravo AF: 0.00384

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;.;.;.;.
Eigen	Benign	0.061
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.89	D;D;.;T;D
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Uncertain	0.016	D
MutationAssessor	Benign	1.4	L;L;.;.;.
MutationTaster	Benign	0.80	N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.76	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.22	B;D;B;D;B
Vest4		0.10
MVP		0.73
MPC		0.53
ClinPred		0.0082	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.37
dbscSNV1_RF	Benign	0.43
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

LitVar

Other links and lift over

dbSNP: rs5172; hg19: chr1-53723993; COSMIC: COSV60101024; COSMIC: COSV60101024;