rs41272110

Variant names:

• chr6-160585140-T-C
• rs41272110
• NM_005577.4:c.4195A>G
• LPA p.Thr1399Ala

Your query was ambiguous. Multiple possible variants found:

• chr6-160585140-T-C
• chr6-160585140-T-G

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• 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: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		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.
	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).

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

Sel.	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	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000399	AC:1	Hom:	AN:250654	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461572	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

Case/control cohorts

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

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar