Genetic Variant NM_005577.4:c.4195A>C (chr6-160585140-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005577.4(LPA):c.4195A>C(p.Thr1399Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,613,538 control chromosomes in the GnomAD database, including 14,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.099 ( 949 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13836 hom. )

Consequence

LPA
NM_005577.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.90

Publications

27 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027101636).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPA	NM_005577.4 link	c.4195A>C	p.Thr1399Pro	missense_variant	Exon 26 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.4195A>C	p.Thr1399Pro	missense_variant	Exon 26 of 39	1	NM_005577.4	ENSP00000321334.6		P08519

Frequencies

GnomAD3 genomes

AF:

0.0990

AC:

15048

AN:

152070

Hom.:

949

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0267

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0898

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.146

Gnomad OTH

AF:

0.0809

GnomAD2 exomes

AF:

0.110

AC:

27534

AN:

250654

AF XY:

0.113

show subpopulations

Gnomad AFR exome

AF:

0.0223

Gnomad AMR exome

AF:

0.0959

Gnomad ASJ exome

AF:

0.131

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.132

AC:

192617

AN:

1461350

Hom.:

13836

Cov.:

AF XY:

0.131

AC XY:

95584

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.0223

AC:

745

AN:

33456

American (AMR)

AF:

0.0968

AC:

4328

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

3471

AN:

26126

East Asian (EAS)

AF:

0.000378

AC:

AN:

39692

South Asian (SAS)

AF:

0.104

AC:

8937

AN:

86254

European-Finnish (FIN)

AF:

0.128

AC:

6841

AN:

53416

Middle Eastern (MID)

AF:

0.0893

AC:

515

AN:

5764

European-Non Finnish (NFE)

AF:

0.145

AC:

160622

AN:

1111566

Other (OTH)

AF:

0.118

AC:

7143

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

8972

17943

26915

35886

44858

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5652

11304

16956

22608

28260

<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:

0.0989

AC:

15053

AN:

152188

Hom.:

949

Cov.:

AF XY:

0.0976

AC XY:

7265

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0266

AC:

1106

AN:

41540

American (AMR)

AF:

0.103

AC:

1579

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

460

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5176

South Asian (SAS)

AF:

0.0909

AC:

438

AN:

4820

European-Finnish (FIN)

AF:

0.126

AC:

1338

AN:

10602

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.146

AC:

9910

AN:

67994

Other (OTH)

AF:

0.0801

AC:

169

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

688

1375

2063

2750

3438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<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:

0.124

Hom.:

2638

Bravo

AF:

0.0931

TwinsUK

AF:

0.139

AC:

515

ALSPAC

AF:

0.153

AC:

591

ESP6500AA

AF:

0.0278

AC:

122

ESP6500EA

AF:

0.149

AC:

1281

ExAC

AF:

0.109

AC:

13205

Asia WGS

AF:

0.0450

AC:

157

AN:

3476

EpiCase

AF:

0.144

EpiControl

AF:

0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.92

Eigen

Benign

0.064

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.43

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.64

PhyloP100

2.9

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.26

Sift

Benign

0.036

Sift4G

Uncertain

0.025

Vest4

0.15

ClinPred

0.042

GERP RS

2.4

gMVP

0.65

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over