Genetic Variant LPA:p.Met1679Thr (chr6-160548597-A-G) – 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.5036T>C(p.Met1679Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,613,680 control chromosomes in the GnomAD database, including 374,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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 0.71 ( 39707 hom., cov: 31)

Exomes 𝑓: 0.67 ( 335094 hom. )

Consequence

LPA
NM_005577.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.935

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 made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.9547696E-7).

BP6

Variant 6-160548597-A-G is Benign according to our data. Variant chr6-160548597-A-G is described in ClinVar as [Benign]. Clinvar id is 1241754.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPA	NM_005577.4 link	c.5036T>C	p.Met1679Thr	missense_variant	Exon 31 of 39	ENST00000316300.10	NP_005568.2	P08519

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPA	ENST00000316300.10 link	c.5036T>C	p.Met1679Thr	missense_variant	Exon 31 of 39	1	NM_005577.4	ENSP00000321334.6		P08519

Frequencies

GnomAD3 genomes

AF:

0.714

AC:

108390

AN:

151792

Hom.:

39670

Cov.:

show subpopulations

Gnomad AFR

AF:

0.864

Gnomad AMI

AF:

0.744

Gnomad AMR

AF:

0.619

Gnomad ASJ

AF:

0.661

Gnomad EAS

AF:

0.455

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.649

Gnomad MID

AF:

0.744

Gnomad NFE

AF:

0.688

Gnomad OTH

AF:

0.681

GnomAD3 exomes

AF:

0.642

AC:

161399

AN:

251250

Hom.:

53235

AF XY:

0.640

AC XY:

86974

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.866

Gnomad AMR exome

AF:

0.544

Gnomad ASJ exome

AF:

0.656

Gnomad EAS exome

AF:

0.452

Gnomad SAS exome

AF:

0.573

Gnomad FIN exome

AF:

0.647

Gnomad NFE exome

AF:

0.688

Gnomad OTH exome

AF:

0.649

GnomAD4 exome

AF:

0.674

AC:

984634

AN:

1461770

Hom.:

335094

Cov.:

AF XY:

0.671

AC XY:

487597

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.874

Gnomad4 AMR exome

AF:

0.554

Gnomad4 ASJ exome

AF:

0.665

Gnomad4 EAS exome

AF:

0.463

Gnomad4 SAS exome

AF:

0.581

Gnomad4 FIN exome

AF:

0.643

Gnomad4 NFE exome

AF:

0.689

Gnomad4 OTH exome

AF:

0.672

GnomAD4 genome

AF:

0.714

AC:

108478

AN:

151910

Hom.:

39707

Cov.:

AF XY:

0.707

AC XY:

52474

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.864

Gnomad4 AMR

AF:

0.619

Gnomad4 ASJ

AF:

0.661

Gnomad4 EAS

AF:

0.455

Gnomad4 SAS

AF:

0.559

Gnomad4 FIN

AF:

0.649

Gnomad4 NFE

AF:

0.688

Gnomad4 OTH

AF:

0.681

Alfa

AF:

0.689

Hom.:

16354

Bravo

AF:

0.715

TwinsUK

AF:

0.689

AC:

2553

ALSPAC

AF:

0.677

AC:

2611

ESP6500AA

AF:

0.865

AC:

3812

ESP6500EA

AF:

0.685

AC:

5894

ExAC

AF:

0.653

AC:

79244

EpiCase

AF:

0.679

EpiControl

AF:

0.678

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26377243) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.5

DANN

Benign

0.18

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.025

MetaRNN

Benign

7.0e-7

MetaSVM

Benign

-0.98

PrimateAI

Benign

0.39

PROVEAN

Benign

4.0

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.030

ClinPred

0.0031

GERP RS

0.73

gMVP

0.80

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

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