4-3514856-C-G

Position:

• chr4-3514856-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_002337.4(LRPAP1):​c.907G>C​(p.Glu303Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: LRPAP1 NM_002337.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09096569).
• BP6: Variant 4-3514856-C-G is Benign according to our data. Variant chr4-3514856-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3539744.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRPAP1	NM_002337.4	c.907G>C	p.Glu303Gln	missense_variant	7/8	ENST00000650182.1	NP_002328.1
LRPAP1	NR_110005.2	n.870G>C		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRPAP1	ENST00000650182.1	c.907G>C	p.Glu303Gln	missense_variant	7/8		NM_002337.4	ENSP00000497444.1
LRPAP1	ENST00000296325.9	n.870G>C		non_coding_transcript_exon_variant	7/8	1
LRPAP1	ENST00000648517.1	n.*399G>C		non_coding_transcript_exon_variant	8/8			ENSP00000496947.1
LRPAP1	ENST00000648517.1	n.*399G>C		3_prime_UTR_variant	8/8			ENSP00000496947.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

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 08, 2024

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	0.090
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.5
DANN	Benign	0.88
DEOGEN2	Benign	0.085	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.44	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.050	N;.
REVEL	Benign	0.12
Sift	Benign	0.81	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.010	B;B
Vest4		0.23
MutPred		0.48		Gain of MoRF binding (P = 0.0204);Gain of MoRF binding (P = 0.0204);
MVP		0.28
MPC		0.058
ClinPred		0.12	T
GERP RS		-1.0
Varity_R		0.15
gMVP		0.14

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: rs765273361; hg19: chr4-3516583;