rs7765781

chr6-160586464-G-C

Variant summary

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

The NM_005577.4(LPA):c.4114C>G(p.Leu1372Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,611,430 control chromosomes in the GnomAD database, including 105,168 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 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 (13897 hom., cov: 32)
  • Exomes 𝑓: 0.35 (91271 hom.)
• Consequence: LPA NM_005577.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6006301E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPA	NM_005577.4	c.4114C>G	p.Leu1372Val	missense_variant	25/39	ENST00000316300.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPA	ENST00000316300.10	c.4114C>G	p.Leu1372Val	missense_variant	25/39	1	NM_005577.4	P1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62681 AN: 151960 Hom.: 13864 Cov.: 32

Gnomad AFR AF: 0.585

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.388

GnomAD3 exomes AF: 0.355 AC: 88414 AN: 249128 Hom.: 16505 AF XY: 0.356 AC XY: 48168 AN XY: 135128

Gnomad AFR exome AF: 0.583

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.395

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: 0.349 AC: 508989 AN: 1459352 Hom.: 91271 Cov.: 44 AF XY: 0.350 AC XY: 253823 AN XY: 726116

Gnomad4 AFR exome AF: 0.584

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.428

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.370

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.362

GnomAD4 genome AF: 0.413 AC: 62777 AN: 152078 Hom.: 13897 Cov.: 32 AF XY: 0.412 AC XY: 30618 AN XY: 74338

Gnomad4 AFR AF: 0.585

Gnomad4 AMR AF: 0.321

Gnomad4 ASJ AF: 0.343

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.344

Gnomad4 OTH AF: 0.394

Alfa AF: 0.359 Hom.: 7593

Bravo AF: 0.414

TwinsUK AF: 0.329 AC: 1221

ALSPAC AF: 0.335 AC: 1293

ESP6500AA AF: 0.560 AC: 2188

ESP6500EA AF: 0.343 AC: 2865

ExAC AF: 0.362 AC: 43787

Asia WGS AF: 0.406 AC: 1409 AN: 3478

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	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.0040
Dann	Benign	0.13
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00042	N
MetaRNN	Benign	0.000016	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.078
Sift	Benign	0.97	T
Sift4G	Benign	0.82	T
Vest4		0.080
ClinPred		0.00080	T
GERP RS		-2.2
gMVP		0.13

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: rs7765781; hg19: chr6-161007496; COSMIC: COSV60296189; COSMIC: COSV60296189;