NM_005577.4:c.4195A>C

Variant names:

• chr6-160585140-T-G
• rs41272110
• NM_005577.4:c.4195A>C
• LPA p.Thr1399Pro

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-9 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -9 classification points (ACMG Germline Pathogenicity v2019). BA1BP4

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 cumulative frequency of 0.129 (AC=207,670) in the gnomAD database across 1,613,538 control chromosomes, including 14,785 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.144. 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. This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• 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
• Publications: 27 publications found

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1439 — exceeds 5%% threshold (BA1 applied)

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>C	p.Thr1399Pro	missense	Exon 26 of 39	NP_005568.2	P08519

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPA	ENST00000316300.10	TSL:1 MANE Select	c.4195A>C	p.Thr1399Pro	missense	Exon 26 of 39	ENSP00000321334.6	P08519
	LPA	ENST00000870146.1		c.4192A>C	p.Thr1398Pro	missense	Exon 26 of 39	ENSP00000540205.1	A0ACI8Q244
	LPA	ENST00000870147.1		c.3877A>C	p.Thr1293Pro	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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0990	AC:15048	Hom:949	AN:152070	Cov:32
GnomAD2 exomes	AF: 0.110	AC:27534	Hom:	AN:250654	Cov:
GnomAD4 exome	AF: 0.132	AC:192617	Hom:13836	AN:1461350	Cov:33
GnomAD4 genome	AF: 0.0989	AC:15053	Hom:949	AN:152188	Cov:32
TOPMed (Bravo)	AF: 0.0931	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.121	AC:41993	Hom:2968	AN:347094	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0901	AC:211	Hom:16	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.00187	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.163	AC:49	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.108	AC:1403	Hom:	AN:12974	Cov:
GenomeAsia100K	AF: 0.0450	AC:157	Hom:	AN:3476	Cov:
Qatari Genome	AF: 0.0909	AC:16	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000570	AC:7	Hom:0	AN:122732	Cov:
Turkish Variome	AF: 0.123	AC:824	Hom:56	AN:6724	Cov:
UK10K	AF: 0.146	AC:1106	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00100	AC:9	Hom:0	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.144 *	1602	11110	0.144 *	2543	17614
BipEx(Bipolar disorder (including schizoaffective))	0.142	4034	28414	0.148	4265	28844
Epi25(Epilepsy)	0.121	5084	41952	0.126	8421	66870
SCHEMA(Schizophrenia)	0.0963	12302	127802	0.115	23813	206790

Showing 4 cohortsAllele 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 pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.26
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
FuncVEP CTI	Benign	0.046
GPN-Star LLR	N/A	-3.9
GPN-Star score	N/A	3.9
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.64	T
Mutation Taster	N/A	98/2	polymorphism (auto)
PhyloP100	Benign	2.9
popEVE	Benign	-3.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.26
Sift	Benign	0.036	D
Sift4G	Uncertain	0.025	D

Showing 22 of 22 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

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.

Other links and lift over

dbSNP: rs41272110;

hg19: chr6-161006172;

COSMIC: COSV60315923;

COSMIC: COSV60315923;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar