6-160585045-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_005577.4(LPA):c.4289+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,613,234 control chromosomes in the GnomAD database, including 1,290 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 111 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1179 hom. )

Consequence

LPA
NM_005577.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:2

Conservation

PhyloP100: 3.51

Publications

52 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

BP6

Variant 6-160585045-C-T is Benign according to our data. Variant chr6-160585045-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPA	NM_005577.4 link	c.4289+1G>A		splice_donor_variant, intron_variant	Intron 26 of 38	ENST00000316300.10	NP_005568.2	P08519

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPA	ENST00000316300.10 link	c.4289+1G>A		splice_donor_variant, intron_variant	Intron 26 of 38	1	NM_005577.4	ENSP00000321334.6		P08519

Frequencies

GnomAD3 genomes

AF:

0.0301

AC:

4571

AN:

152072

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00746

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0584

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0369

Gnomad FIN

AF:

0.0529

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0364

Gnomad OTH

AF:

0.0253

GnomAD2 exomes

AF:

0.0405

AC:

10118

AN:

249794

AF XY:

0.0388

show subpopulations

Gnomad AFR exome

AF:

0.00709

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.0269

Gnomad EAS exome

AF:

0.000990

Gnomad FIN exome

AF:

0.0468

Gnomad NFE exome

AF:

0.0339

Gnomad OTH exome

AF:

0.0370

GnomAD4 exome

AF:

0.0367

AC:

53600

AN:

1461044

Hom.:

1179

Cov.:

AF XY:

0.0363

AC XY:

26406

AN XY:

726870

show subpopulations

African (AFR)

AF:

0.00583

AC:

195

AN:

33436

American (AMR)

AF:

0.0978

AC:

4374

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0260

AC:

680

AN:

26112

East Asian (EAS)

AF:

0.000580

AC:

AN:

39682

South Asian (SAS)

AF:

0.0339

AC:

2925

AN:

86246

European-Finnish (FIN)

AF:

0.0478

AC:

2552

AN:

53414

Middle Eastern (MID)

AF:

0.0296

AC:

170

AN:

5750

European-Non Finnish (NFE)

AF:

0.0365

AC:

40576

AN:

1111352

Other (OTH)

AF:

0.0349

AC:

2105

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2454

4908

7363

9817

12271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1602

3204

4806

6408

8010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0300

AC:

4572

AN:

152190

Hom.:

111

Cov.:

AF XY:

0.0313

AC XY:

2331

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00744

AC:

309

AN:

41550

American (AMR)

AF:

0.0582

AC:

889

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.0371

AC:

179

AN:

4822

European-Finnish (FIN)

AF:

0.0529

AC:

559

AN:

10576

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0365

AC:

2480

AN:

68008

Other (OTH)

AF:

0.0250

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

234

469

703

938

1172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0318

Hom.:

362

Bravo

AF:

0.0304

TwinsUK

AF:

0.0332

AC:

123

ALSPAC

AF:

0.0371

AC:

143

ESP6500AA

AF:

0.00732

AC:

ESP6500EA

AF:

0.0346

AC:

295

ExAC

AF:

0.0369

AC:

4478

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0335

EpiControl

AF:

0.0344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lipoprotein(a) deficiency, congenital

Pathogenic:1

Aug 07, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

LPA-related disorder

Benign:1

Mar 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Benign

0.93

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.75

PhyloP100

3.5

GERP RS

2.6

Mutation Taster

=29/71

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.52

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over