rs7765803

Positions:

• chr6-160586506-G-C
• chr6-160586506-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005577.4(LPA):​c.4072C>G​(p.Leu1358Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,613,150 control chromosomes in the GnomAD database, including 103,992 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.41 (13236 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90756 hom.)
• Consequence: LPA NM_005577.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.09

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.1662784E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPA	NM_005577.4	c.4072C>G	p.Leu1358Val	missense_variant	25/39	ENST00000316300.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPA	ENST00000316300.10	c.4072C>G	p.Leu1358Val	missense_variant	25/39	1	NM_005577.4	P1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61511 AN: 151940 Hom.: 13206 Cov.: 32

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.385

GnomAD3 exomes AF: 0.353 AC: 88052 AN: 249370 Hom.: 16264 AF XY: 0.355 AC XY: 48028 AN XY: 135272

Gnomad AFR exome AF: 0.555

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.396

Gnomad SAS exome AF: 0.377

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.343

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.348 AC: 508819 AN: 1461092 Hom.: 90756 Cov.: 51 AF XY: 0.349 AC XY: 253736 AN XY: 726868

Gnomad4 AFR exome AF: 0.556

Gnomad4 AMR exome AF: 0.256

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.429

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.370

Gnomad4 NFE exome AF: 0.339

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.405 AC: 61603 AN: 152058 Hom.: 13236 Cov.: 32 AF XY: 0.404 AC XY: 30048 AN XY: 74308

Gnomad4 AFR AF: 0.558

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.400

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.344

Gnomad4 OTH AF: 0.391

Alfa AF: 0.311 Hom.: 2348

Bravo AF: 0.405

TwinsUK AF: 0.329 AC: 1221

ALSPAC AF: 0.335 AC: 1293

ESP6500AA AF: 0.533 AC: 2242

ESP6500EA AF: 0.344 AC: 2935

ExAC AF: 0.360 AC: 43565

Asia WGS AF: 0.405 AC: 1406 AN: 3476

EpiCase AF: 0.350

EpiControl AF: 0.333

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0030
DANN	Benign	0.048
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00092	N
MetaRNN	Benign	0.000072	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.24	N;.
REVEL	Benign	0.047
Sift	Benign	1.0	T;.
Sift4G	Benign	0.85	T;T
Vest4		0.016
MPC		0.037
ClinPred		0.0015	T
GERP RS		-2.6
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs7765803; hg19: chr6-161007538; COSMIC: COSV60303226;