chr6-160548597-A-G

Variant names:

• chr6-160548597-A-G
• rs1801693
• NM_005577.4:c.5036T>C

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.5036T>C​(p.Met1679Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,613,680 control chromosomes in the GnomAD database, including 374,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict 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. M1679I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.71 (39707 hom., cov: 31)
  • Exomes 𝑓: 0.67 (335094 hom.)
• Consequence: LPA NM_005577.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.935
• Publications: 37 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=6.9547696E-7).
• BP6: Variant 6-160548597-A-G is Benign according to our data. Variant chr6-160548597-A-G is described in ClinVar as Benign. ClinVar VariationId is 1241754.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPA	NM_005577.4	c.5036T>C	p.Met1679Thr	missense_variant	Exon 31 of 39	ENST00000316300.10	NP_005568.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPA	ENST00000316300.10	c.5036T>C	p.Met1679Thr	missense_variant	Exon 31 of 39	1	NM_005577.4	ENSP00000321334.6

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108390 AN: 151792 Hom.: 39670 Cov.: 31

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.744

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.681

GnomAD2 exomes AF: 0.642 AC: 161399 AN: 251250 AF XY: 0.640

Gnomad AFR exome AF: 0.866

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.656

Gnomad EAS exome AF: 0.452

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.674 AC: 984634 AN: 1461770 Hom.: 335094 Cov.: 55 AF XY: 0.671 AC XY: 487597 AN XY: 727182

African (AFR) AF: 0.874 AC: 29259 AN: 33476

American (AMR) AF: 0.554 AC: 24789 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 17371 AN: 26134

East Asian (EAS) AF: 0.463 AC: 18365 AN: 39696

South Asian (SAS) AF: 0.581 AC: 50091 AN: 86256

European-Finnish (FIN) AF: 0.643 AC: 34357 AN: 53414

Middle Eastern (MID) AF: 0.690 AC: 3976 AN: 5760

European-Non Finnish (NFE) AF: 0.689 AC: 765828 AN: 1111920

Other (OTH) AF: 0.672 AC: 40598 AN: 60390

GnomAD4 genome AF: 0.714 AC: 108478 AN: 151910 Hom.: 39707 Cov.: 31 AF XY: 0.707 AC XY: 52474 AN XY: 74256

African (AFR) AF: 0.864 AC: 35786 AN: 41412

American (AMR) AF: 0.619 AC: 9439 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2295 AN: 3472

East Asian (EAS) AF: 0.455 AC: 2344 AN: 5150

South Asian (SAS) AF: 0.559 AC: 2678 AN: 4794

European-Finnish (FIN) AF: 0.649 AC: 6851 AN: 10558

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.688 AC: 46759 AN: 67956

Other (OTH) AF: 0.681 AC: 1435 AN: 2108

Alfa AF: 0.688 Hom.: 22549

Bravo AF: 0.715

TwinsUK AF: 0.689 AC: 2553

ALSPAC AF: 0.677 AC: 2611

ESP6500AA AF: 0.865 AC: 3812

ESP6500EA AF: 0.685 AC: 5894

ExAC AF: 0.653 AC: 79244

EpiCase AF: 0.679

EpiControl AF: 0.678

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26377243) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.5
DANN	Benign	0.18
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.025	N
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.94
PrimateAI	Benign	0.39	T
PROVEAN	Benign	4.0	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.030
ClinPred		0.0031	T
GERP RS		0.73
gMVP		0.80
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801693; hg19: chr6-160969629; COSMIC: COSV60307477;