4-3512968-A-G

Variant names:

• chr4-3512968-A-G
• rs6789
• ENST00000296325.9:n.1043T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000296325.9(LRPAP1):​n.1043T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,605,270 control chromosomes in the GnomAD database, including 90,580 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8484 hom., cov: 34)
  • Exomes 𝑓: 0.33 (82096 hom.)
• Consequence: LRPAP1 ENST00000296325.9 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.298
• Publications: 25 publications found

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]

LRPAP1 Gene-Disease associations (from GenCC):

• myopia 23, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000296325.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPAP1	NM_002337.4	MANE Select	c.*6T>C		3_prime_UTR	Exon 8 of 8	NP_002328.1
	LRPAP1	NR_110005.2		n.1043T>C		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPAP1	ENST00000296325.9	TSL:1	n.1043T>C		non_coding_transcript_exon	Exon 8 of 8
	LRPAP1	ENST00000650182.1	MANE Select	c.*6T>C		3_prime_UTR	Exon 8 of 8	ENSP00000497444.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49472 AN: 152044 Hom.: 8465 Cov.: 34

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.311

GnomAD2 exomes AF: 0.366 AC: 86976 AN: 237522 AF XY: 0.365

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.584

Gnomad ASJ exome AF: 0.290

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.328 AC: 477109 AN: 1453108 Hom.: 82096 Cov.: 33 AF XY: 0.333 AC XY: 240718 AN XY: 722226

African (AFR) AF: 0.286 AC: 9515 AN: 33258

American (AMR) AF: 0.573 AC: 24903 AN: 43490

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 7474 AN: 26004

East Asian (EAS) AF: 0.413 AC: 16217 AN: 39258

South Asian (SAS) AF: 0.508 AC: 42968 AN: 84570

European-Finnish (FIN) AF: 0.243 AC: 12858 AN: 52916

Middle Eastern (MID) AF: 0.354 AC: 2035 AN: 5744

European-Non Finnish (NFE) AF: 0.308 AC: 341335 AN: 1107770

Other (OTH) AF: 0.330 AC: 19804 AN: 60098

GnomAD4 genome AF: 0.325 AC: 49528 AN: 152162 Hom.: 8484 Cov.: 34 AF XY: 0.331 AC XY: 24661 AN XY: 74408

African (AFR) AF: 0.285 AC: 11843 AN: 41518

American (AMR) AF: 0.475 AC: 7267 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1042 AN: 3470

East Asian (EAS) AF: 0.410 AC: 2122 AN: 5180

South Asian (SAS) AF: 0.502 AC: 2420 AN: 4820

European-Finnish (FIN) AF: 0.247 AC: 2611 AN: 10570

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21152 AN: 67984

Other (OTH) AF: 0.309 AC: 653 AN: 2110

Alfa AF: 0.320 Hom.: 19087

Bravo AF: 0.337

Asia WGS AF: 0.407 AC: 1413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.80
DANN	Benign	0.50
PhyloP100		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6789; hg19: chr4-3514695; COSMIC: COSV56347184; COSMIC: COSV56347184;