chr6-160542742-C-G

Variant names:

• chr6-160542742-C-G
• rs41265936
• NM_005577.4:c.5465G>C

Variant summary

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

The NM_005577.4(LPA):​c.5465G>C​(p.Gly1822Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,614,044 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (87 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (94 hom.)
• Consequence: LPA NM_005577.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10

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=0.0058689117).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPA	NM_005577.4	c.5465G>C	p.Gly1822Ala	missense_variant	Exon 34 of 39	ENST00000316300.10	NP_005568.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPA	ENST00000316300.10	c.5465G>C	p.Gly1822Ala	missense_variant	Exon 34 of 39	1	NM_005577.4	ENSP00000321334.6

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2735 AN: 152096 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00495 AC: 1244 AN: 251448 Hom.: 45 AF XY: 0.00377 AC XY: 513 AN XY: 135906

Gnomad AFR exome AF: 0.0640

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00198 AC: 2892 AN: 1461830 Hom.: 94 Cov.: 31 AF XY: 0.00173 AC XY: 1260 AN XY: 727220

Gnomad4 AFR exome AF: 0.0655

Gnomad4 AMR exome AF: 0.00364

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.0181 AC: 2748 AN: 152214 Hom.: 87 Cov.: 32 AF XY: 0.0178 AC XY: 1323 AN XY: 74432

Gnomad4 AFR AF: 0.0627

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.000779 Hom.: 0

Bravo AF: 0.0198

ESP6500AA AF: 0.0635 AC: 280

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00619 AC: 751

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.11
Eigen	Benign	0.16
Eigen_PC	Benign	-0.067
FATHMM_MKL	Benign	0.48	N
MetaRNN	Benign	0.0059	T
MetaSVM	Uncertain	0.31	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.45
Sift	Benign	0.064	T
Sift4G	Uncertain	0.017	D
Vest4		0.39
MVP		0.54
ClinPred		0.079	T
GERP RS		2.5
gMVP		0.38

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: rs41265936; hg19: chr6-160963774;