4-3518154-C-T

Position:

• chr4-3518154-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002337.4(LRPAP1):​c.631G>A​(p.Asp211Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,613,456 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: LRPAP1 NM_002337.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.28

Genes affected

LRPAP1 (HGNC:6701): (LDL receptor related protein associated protein 1) This gene encodes a protein that interacts with the low density lipoprotein (LDL) receptor-related protein and facilitates its proper folding and localization by preventing the binding of ligands. Mutations in this gene have been identified in individuals with myopia 23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004767418).
• BP6: Variant 4-3518154-C-T is Benign according to our data. Variant chr4-3518154-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 770708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRPAP1	NM_002337.4	c.631G>A	p.Asp211Asn	missense_variant	5/8	ENST00000650182.1	NP_002328.1
LRPAP1	NR_110005.2	n.594G>A		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRPAP1	ENST00000650182.1	c.631G>A	p.Asp211Asn	missense_variant	5/8		NM_002337.4	ENSP00000497444	P1

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00719

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00249 AC: 625 AN: 250676 Hom.: 2 AF XY: 0.00234 AC XY: 317 AN XY: 135662

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00444

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00354 AC: 5172 AN: 1461124 Hom.: 15 Cov.: 31 AF XY: 0.00347 AC XY: 2525 AN XY: 726854

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00570

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.000226

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00259 AC XY: 193 AN XY: 74496

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00337 Hom.: 5

Bravo AF: 0.00377

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00205 AC: 249

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00397

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

LRPAP1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.097	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.40	.;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.79	N;.
REVEL	Benign	0.066
Sift	Benign	0.12	T;.
Sift4G	Benign	0.42	T;.
Polyphen		0.47	P;P
Vest4		0.10
MVP		0.19
MPC		0.066
ClinPred		0.0028	T
GERP RS		-0.022
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs111244551; hg19: chr4-3519881; COSMIC: COSV99578981;