chr6:160585140-T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 10/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.099 (949 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13836 hom.)
• Consequence: LPA NM_005577.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
LPA	NM_005577.4	c.4195A>C	p.Thr1399Pro	missense_variant	26/39	ENST00000316300.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPA	ENST00000316300.10	c.4195A>C	p.Thr1399Pro	missense_variant	26/39	1	NM_005577.4	P1

Frequencies

GnomAD3 genomes AF: 0.0990 AC: 15048 AN: 152070 Hom.: 949 Cov.: 32

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

GnomAD3 exomes AF: 0.110 AC: 27534 AN: 250654 Hom.: 1883 AF XY: 0.113 AC XY: 15278 AN XY: 135758

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 SAS exome AF: 0.100

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.: 33 AF XY: 0.131 AC XY: 95584 AN XY: 727010

Gnomad4 AFR exome AF: 0.0223

Gnomad4 AMR exome AF: 0.0968

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.0989 AC: 15053 AN: 152188 Hom.: 949 Cov.: 32 AF XY: 0.0976 AC XY: 7265 AN XY: 74422

Gnomad4 AFR AF: 0.0266

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0909

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.0801

Alfa AF: 0.125 Hom.: 1881

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

BayesDel_addAF

Benign

-0.52

T

BayesDel_noAF

Benign

-0.38

Cadd

Benign

22

Dann

Benign

0.92

Eigen

Benign

0.064

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.43

N

MetaRNN

Benign

0.0027

T

MetaSVM

Benign

-0.64

T

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.49

T

PROVEAN

Uncertain

-2.9

D

REVEL

Benign

0.26

Sift

Benign

0.036

D

Sift4G

Uncertain

0.025

D

Vest4

0.15

ClinPred

0.042

T

GERP RS

2.4

gMVP

0.65

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

Other links and lift over

dbSNP: rs41272110; hg19: chr6-161006172; COSMIC: COSV60315923; COSMIC: COSV60315923;