Genetic Variant LPA:p.Thr1399Ala (chr6-160585138-TGT-GGC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_005577.4(LPA):c.4195_4197delACAinsGCC (p.Thr1399Ala) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

LPA
NM_005577.4 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.90

Publications

0 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:

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new If you want to explore the variant's impact on the transcript NM_005577.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005577.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LPA NM_005577.4	MANE Select	c.4195_4197delACAinsGCC p.Thr1399Ala	missense	N/A	Prot: NP_005568.2 UniProt: P08519

LPA NM_005577.4

MANE Select

HGVSc / HGVSpc.4195_4197delACAinsGCCp.Thr1399Ala

Exon rankN/A

missense

Prot: NP_005568.2UniProt: P08519

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
LPA ENST00000316300.10	TSL:1MANE Select	c.4195_4197delACAinsGCC p.Thr1399Ala	missense	N/A	Prot: ENSP00000321334.6 UniProt: P08519
LPA ENST00000870146.1		c.4192_4194delACAinsGCC p.Thr1398Ala	missense	N/A	Prot: ENSP00000540205.1 UniProt: A0ACI8Q244
LPA ENST00000870147.1		c.3877_3879delACAinsGCC p.Thr1293Ala	missense	N/A	Prot: ENSP00000540206.1 UniProt: A0ACI8R6G4

LPA ENST00000316300.10

TSL:1MANE Select

HGVSc / HGVSpc.4195_4197delACAinsGCCp.Thr1399Ala

Exon rankN/A

missense

Prot: ENSP00000321334.6UniProt: P08519

LPA ENST00000870146.1

HGVSc / HGVSpc.4192_4194delACAinsGCCp.Thr1398Ala

Exon rankN/A

missense

Prot: ENSP00000540205.1UniProt: A0ACI8Q244

LPA ENST00000870147.1

HGVSc / HGVSpc.3877_3879delACAinsGCCp.Thr1293Ala

Exon rankN/A

missense

Prot: ENSP00000540206.1UniProt: A0ACI8R6G4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence