4-3516207-G-T

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.752-9C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: LRPAP1 NM_002337.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004593
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.402

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 (BayesDel_noAF=-0.81).
• BP6: Variant 4-3516207-G-T is Benign according to our data. Variant chr4-3516207-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3049703.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.752-9C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000650182.1
LRPAP1	NR_110005.2	n.715-9C>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRPAP1	ENST00000650182.1	c.752-9C>A		splice_polypyrimidine_tract_variant, intron_variant			NM_002337.4	P1
LRPAP1	ENST00000296325.9	n.715-9C>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
LRPAP1	ENST00000515119.5	c.*529-9C>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2
LRPAP1	ENST00000648517.1	c.*244-9C>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408714 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 695748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

LRPAP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2019

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
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.1
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-3517934;