6-160545458-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005577.4(LPA):ā€‹c.5380T>Cā€‹(p.Cys1794Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,456,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

LPA
NM_005577.4 missense

Scores

7
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.60
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LPANM_005577.4 linkc.5380T>C p.Cys1794Arg missense_variant Exon 33 of 39 ENST00000316300.10 NP_005568.2 P08519

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LPAENST00000316300.10 linkc.5380T>C p.Cys1794Arg missense_variant Exon 33 of 39 1 NM_005577.4 ENSP00000321334.6 P08519

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1456432
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
724916
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 14, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.5380T>C (p.C1794R) alteration is located in exon 34 (coding exon 33) of the LPA gene. This alteration results from a T to C substitution at nucleotide position 5380, causing the cysteine (C) at amino acid position 1794 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
27
DANN
Benign
0.96
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.93
D
M_CAP
Benign
0.043
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.95
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-10
D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0030
D
Vest4
0.93
MVP
0.64
ClinPred
1.0
D
GERP RS
2.7
gMVP
0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-160966490; COSMIC: COSV60306815; API