Genetic Variant LPA:p.Arg2016Cys (chr6-160531806-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005577.4(LPA):c.6046C>T(p.Arg2016Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,613,340 control chromosomes in the GnomAD database, including 57,872 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.25 ( 4842 hom., cov: 32)

Exomes 𝑓: 0.27 ( 53030 hom. )

Consequence

LPA
NM_005577.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.01

Variant links:

Genes affected

LPA (HGNC:6667): (lipoprotein(a)) The protein encoded by this gene is a serine proteinase that inhibits the activity of tissue-type plasminogen activator I. The encoded protein constitutes a substantial portion of lipoprotein(a) and is proteolytically cleaved, resulting in fragments that attach to atherosclerotic lesions and promote thrombogenesis. Elevated plasma levels of this protein are linked to atherosclerosis. Depending on the individual, the encoded protein contains 2-43 copies of kringle-type domains. The allele represented here contains 15 copies of the kringle-type repeats and corresponds to that found in the reference genome sequence. [provided by RefSeq, Dec 2009]

LPA links:

LOC124901454 (HGNC:):

LOC124901454 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004955858).

BP6

Variant 6-160531806-G-A is Benign according to our data. Variant chr6-160531806-G-A is described in ClinVar as [Benign]. Clinvar id is 1251319.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPA	NM_005577.4 link	c.6046C>T	p.Arg2016Cys	missense_variant	Exon 39 of 39	ENST00000316300.10	NP_005568.2	P08519
LOC124901454	XR_007059844.1 link	n.484-7711G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPA	ENST00000316300.10 link	c.6046C>T	p.Arg2016Cys	missense_variant	Exon 39 of 39	1	NM_005577.4	ENSP00000321334.6		P08519

Frequencies

GnomAD3 genomes

AF:

0.247

AC:

37469

AN:

151880

Hom.:

4844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.228

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.266

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.297

Gnomad MID

AF:

0.239

Gnomad NFE

AF:

0.277

Gnomad OTH

AF:

0.237

GnomAD3 exomes

AF:

0.237

AC:

59707

AN:

251420

Hom.:

7775

AF XY:

0.240

AC XY:

32576

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.236

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.264

Gnomad EAS exome

AF:

0.125

Gnomad SAS exome

AF:

0.206

Gnomad FIN exome

AF:

0.301

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.248

GnomAD4 exome

AF:

0.265

AC:

387733

AN:

1461342

Hom.:

53030

Cov.:

AF XY:

0.264

AC XY:

191978

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.239

Gnomad4 AMR exome

AF:

0.131

Gnomad4 ASJ exome

AF:

0.267

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.207

Gnomad4 FIN exome

AF:

0.299

Gnomad4 NFE exome

AF:

0.281

Gnomad4 OTH exome

AF:

0.254

GnomAD4 genome

AF:

0.246

AC:

37467

AN:

151998

Hom.:

4842

Cov.:

AF XY:

0.245

AC XY:

18164

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.228

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.266

Gnomad4 EAS

AF:

0.118

Gnomad4 SAS

AF:

0.196

Gnomad4 FIN

AF:

0.297

Gnomad4 NFE

AF:

0.277

Gnomad4 OTH

AF:

0.235

Alfa

AF:

0.264

Hom.:

1775

Bravo

AF:

0.235

TwinsUK

AF:

0.286

AC:

1062

ALSPAC

AF:

0.279

AC:

1074

ESP6500AA

AF:

0.233

AC:

1026

ESP6500EA

AF:

0.276

AC:

2377

ExAC

AF:

0.245

AC:

29796

Asia WGS

AF:

0.139

AC:

485

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30389748) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Benign

0.97

Eigen

Benign

-0.076

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.24

MetaRNN

Benign

0.0050

MetaSVM

Uncertain

0.35

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.33

Sift

Benign

0.039

Sift4G

Benign

0.22

Vest4

0.12

ClinPred

0.017

GERP RS

3.0

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over