6-160545527-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005577.4(LPA):c.5311C>T(p.Arg1771Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,610,458 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: LPA NM_005577.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.85

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028131515).
• BP6: Variant 6-160545527-G-A is Benign according to our data. Variant chr6-160545527-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2673089.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPA	NM_005577.4	c.5311C>T	p.Arg1771Cys	missense_variant	33/39	ENST00000316300.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPA	ENST00000316300.10	c.5311C>T	p.Arg1771Cys	missense_variant	33/39	1	NM_005577.4	P1

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 546 AN: 151988 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00571

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00200 AC: 503 AN: 251432 Hom.: 5 AF XY: 0.00173 AC XY: 235 AN XY: 135886

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00124 AC: 1805 AN: 1458352 Hom.: 8 Cov.: 30 AF XY: 0.00125 AC XY: 905 AN XY: 725768

Gnomad4 AFR exome AF: 0.00928

Gnomad4 AMR exome AF: 0.00463

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000885

Gnomad4 OTH exome AF: 0.00312

GnomAD4 genome AF: 0.00358 AC: 545 AN: 152106 Hom.: 4 Cov.: 31 AF XY: 0.00331 AC XY: 246 AN XY: 74336

Gnomad4 AFR AF: 0.00887

Gnomad4 AMR AF: 0.00570

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00164 Hom.: 1

Bravo AF: 0.00449

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00192 AC: 233

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

LPA: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.60	D
MetaRNN	Benign	0.028	T
MetaSVM	Pathogenic	0.85	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.81
MVP		0.59
ClinPred		0.085	T
GERP RS		1.8
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs139145675; hg19: chr6-160966559; COSMIC: COSV60305721;