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

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

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
• BA1: 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	0.0990	15048	949	152070	32
GnomAD2 exomes	0.110	27534		250654
GnomAD4 exome	0.132	192617	13836	1461350	33
GnomAD4 genome	0.0989	15053	949	152188	32
TOPMed (Bravo)	0.0931
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.121	41993	2968	347094
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.0901	211	16	2342
ChinaMAP Phase 1	0.00187
Denmark Genome	0.163	49		300
ESP6500 (Exome Variant Server)	0.108	1403		12974
GenomeAsia100K	0.0450	157		3476
Qatari Genome	0.0909	16		176
ToMMo 61KJPN (+60KJPN MNV)	0.0000570	7	0	122732
Turkish Variome	0.123	824	56	6724
UK10K	0.146	1106		7562
WBBC (Westlake BioBank for Chinese) pilot	0.00100	9	0	8960

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 prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	22
AlphaMissense	Benign	-	0.26
BayesDel_addAF	Benign	T	-0.52
BayesDel_noAF	Benign	-	-0.38
CADD	Benign	-	22
DANN	Benign	-	0.92
Eigen	Benign	-	0.064
Eigen_PC	Benign	-	-0.18
FATHMM_MKL	Benign	N	0.43
FuncVEP CTI	Benign	-	0.046
GPN-Star LLR	N/A	-	-3.9
GPN-Star score	N/A	-	3.9
MetaRNN	Benign	T	0.0027
MetaSVM	Benign	T	-0.64
Mutation Taster	N/A	polymorphism (auto)	98/2
PhyloP100	Benign	-	2.9
popEVE	Benign	-	-3.0
PrimateAI	Uncertain	T	0.49
PROVEAN	Uncertain	D	-2.9
REVEL	Benign	-	0.26
Sift	Benign	D	0.036
Sift4G	Uncertain	D	0.025

Showing 22 of 22 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
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.

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