NM_005577.4:c.4195A>G

Variant names:

Variant summary

Our verdict is The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4

The NM_005577.4(LPA):c.4195A>G (p.Thr1399Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,572 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 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:

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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 1 points.

PM2

Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AR gene (threshold 0.001) — PM2 moderate.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

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.4195A>G	p.Thr1399Ala	missense	Exon 26 of 39	NP_005568.2	P08519

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPA	ENST00000316300.10	TSL:1 MANE Select	c.4195A>G	p.Thr1399Ala	missense	Exon 26 of 39	ENSP00000321334.6	P08519
LPA	ENST00000870146.1		c.4192A>G	p.Thr1398Ala	missense	Exon 26 of 39	ENSP00000540205.1	A0ACI8Q244
LPA	ENST00000870147.1		c.3877A>G	p.Thr1293Ala	missense	Exon 24 of 37	ENSP00000540206.1	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 4 sources Large-scale international reference populations
GnomAD3 genomes					32
GnomAD2 exomes	0.00000399	1		250654
GnomAD4 exome	6.84e-7	1	0	1461572	33
GnomAD4 genome					32

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
Cohort	AF	AC	AN	AF	AC	AN
Epi25 (Epilepsy)	0.0000238	1	41952	0.00	0	66872

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	21
AlphaMissense	Benign	-	0.18
BayesDel_addAF	Benign	T	-0.086
BayesDel_noAF	Benign	-	-0.36
CADD	Benign	-	19
DANN	Uncertain	-	0.97
Eigen	Benign	-	0.051
Eigen_PC	Benign	-	-0.19
FATHMM_MKL	Benign	N	0.38
FuncVEP CTI	Benign	-	0.064
GPN-Star LLR	N/A	-	-3.4
GPN-Star score	N/A	-	3.4
M_CAP	Benign	T	0.0097
MetaRNN	Benign	T	0.28
MetaSVM	Benign	T	-0.89
Mutation Taster	N/A	polymorphism	98/2
PhyloP100	Benign	-	2.9
popEVE	Benign	-	-3.1
PrimateAI	Benign	T	0.48
PROVEAN	Benign	N	-2.2
REVEL	Benign	-	0.28
Sift	Benign	T	0.069
Sift4G	Uncertain	D	0.024

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.010
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

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.

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

Case/control cohorts

ClinVar

Computational Scores

Splicing Scores

Publications

Other links and lift over