6-160531806-G-A

Variant names:

• chr6-160531806-G-A
• rs3124784
• NM_005577.4:c.6046C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005577.4(LPA):​c.6046C>T​(p.Arg2016Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,613,340 control chromosomes in the GnomAD database, including 57,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2016H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (4842 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53030 hom.)
• Consequence: LPA NM_005577.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.01
• Publications: 23 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]

LOC124901454 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004955858).
• BP6: Variant 6-160531806-G-A is Benign according to our data. Variant chr6-160531806-G-A is described in ClinVar as [Benign]. Clinvar id is 1251319.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPA	NM_005577.4	c.6046C>T	p.Arg2016Cys	missense_variant	Exon 39 of 39	ENST00000316300.10	NP_005568.2
LOC124901454	XR_007059844.1	n.484-7711G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPA	ENST00000316300.10	c.6046C>T	p.Arg2016Cys	missense_variant	Exon 39 of 39	1	NM_005577.4	ENSP00000321334.6

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37469 AN: 151880 Hom.: 4844 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.237 AC: 59707 AN: 251420 AF XY: 0.240

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.265 AC: 387733 AN: 1461342 Hom.: 53030 Cov.: 36 AF XY: 0.264 AC XY: 191978 AN XY: 726984

African (AFR) AF: 0.239 AC: 7998 AN: 33448

American (AMR) AF: 0.131 AC: 5851 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6970 AN: 26128

East Asian (EAS) AF: 0.109 AC: 4314 AN: 39696

South Asian (SAS) AF: 0.207 AC: 17821 AN: 86246

European-Finnish (FIN) AF: 0.299 AC: 15971 AN: 53418

Middle Eastern (MID) AF: 0.257 AC: 1480 AN: 5766

European-Non Finnish (NFE) AF: 0.281 AC: 312020 AN: 1111548

Other (OTH) AF: 0.254 AC: 15308 AN: 60386

GnomAD4 genome AF: 0.246 AC: 37467 AN: 151998 Hom.: 4842 Cov.: 32 AF XY: 0.245 AC XY: 18164 AN XY: 74278

African (AFR) AF: 0.228 AC: 9435 AN: 41430

American (AMR) AF: 0.180 AC: 2750 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 921 AN: 3466

East Asian (EAS) AF: 0.118 AC: 608 AN: 5164

South Asian (SAS) AF: 0.196 AC: 945 AN: 4828

European-Finnish (FIN) AF: 0.297 AC: 3134 AN: 10546

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.277 AC: 18835 AN: 67974

Other (OTH) AF: 0.235 AC: 496 AN: 2108

Alfa AF: 0.264 Hom.: 1775

Bravo AF: 0.235

TwinsUK AF: 0.286 AC: 1062

ALSPAC AF: 0.279 AC: 1074

ESP6500AA AF: 0.233 AC: 1026

ESP6500EA AF: 0.276 AC: 2377

ExAC AF: 0.245 AC: 29796

Asia WGS AF: 0.139 AC: 485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30389748) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Benign	0.97
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.0050	T
MetaSVM	Uncertain	0.35	D
PhyloP100		3.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.33
Sift	Benign	0.039	D
Sift4G	Benign	0.22	T
Vest4		0.12
ClinPred		0.017	T
GERP RS		3.0
gMVP		0.40
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3124784; hg19: chr6-160952838; COSMIC: COSV60302204;