4-3516145-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002337.4(LRPAP1):c.805C>T(p.Leu269Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,582,288 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: LRPAP1 NM_002337.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.35

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04671046).
• BP6: Variant 4-3516145-G-A is Benign according to our data. Variant chr4-3516145-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3120352.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRPAP1	NM_002337.4	c.805C>T	p.Leu269Phe	missense_variant	6/8	ENST00000650182.1
LRPAP1	NR_110005.2	n.768C>T		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRPAP1	ENST00000650182.1	c.805C>T	p.Leu269Phe	missense_variant	6/8		NM_002337.4	P1
LRPAP1	ENST00000296325.9	n.768C>T		non_coding_transcript_exon_variant	6/8	1
LRPAP1	ENST00000515119.5	c.*582C>T		3_prime_UTR_variant, NMD_transcript_variant	6/6	2
LRPAP1	ENST00000648517.1	c.*297C>T		3_prime_UTR_variant, NMD_transcript_variant	7/8

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152248 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000191

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000150 AC: 30 AN: 199560 Hom.: 0 AF XY: 0.000140 AC XY: 15 AN XY: 106764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000581

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.000236 AC: 338 AN: 1430040 Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 158 AN XY: 708102

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.000127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000792

Gnomad4 NFE exome AF: 0.000276

Gnomad4 OTH exome AF: 0.000405

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152248 Hom.: 0 Cov.: 34 AF XY: 0.000108 AC XY: 8 AN XY: 74386

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	9.1
Dann	Benign	0.076
DEOGEN2	Benign	0.093	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.46	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.93	N;N
MutationTaster	Benign	0.78	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	4.0	N;.
REVEL	Benign	0.081
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0050	B;B
Vest4		0.30
MVP		0.067
MPC		0.060
ClinPred		0.016	T
GERP RS		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.32

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: rs763387331; hg19: chr4-3517872;