NM_005577.4:c.4195A>C

Variant names:

• chr6-160585140-T-G
• rs41272110
• NM_005577.4:c.4195A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005577.4(LPA):​c.4195A>C​(p.Thr1399Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,613,538 control chromosomes in the GnomAD database, including 14,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.099 (949 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13836 hom.)
• Consequence: LPA NM_005577.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027101636).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPA	NM_005577.4	c.4195A>C	p.Thr1399Pro	missense_variant	Exon 26 of 39	ENST00000316300.10	NP_005568.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPA	ENST00000316300.10	c.4195A>C	p.Thr1399Pro	missense_variant	Exon 26 of 39	1	NM_005577.4	ENSP00000321334.6

Frequencies

GnomAD3 genomes AF: 0.0990 AC: 15048 AN: 152070 Hom.: 949 Cov.: 32

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0898

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.0809

GnomAD2 exomes AF: 0.110 AC: 27534 AN: 250654 AF XY: 0.113

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.0959

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.132 AC: 192617 AN: 1461350 Hom.: 13836 Cov.: 33 AF XY: 0.131 AC XY: 95584 AN XY: 727010

Gnomad4 AFR exome AF: 0.0223 AC: 745 AN: 33456

Gnomad4 AMR exome AF: 0.0968 AC: 4328 AN: 44714

Gnomad4 ASJ exome AF: 0.133 AC: 3471 AN: 26126

Gnomad4 EAS exome AF: 0.000378 AC: 15 AN: 39692

Gnomad4 SAS exome AF: 0.104 AC: 8937 AN: 86254

Gnomad4 FIN exome AF: 0.128 AC: 6841 AN: 53416

Gnomad4 NFE exome AF: 0.145 AC: 160622 AN: 1111566

Gnomad4 Remaining exome AF: 0.118 AC: 7143 AN: 60362

GnomAD4 genome AF: 0.0989 AC: 15053 AN: 152188 Hom.: 949 Cov.: 32 AF XY: 0.0976 AC XY: 7265 AN XY: 74422

Gnomad4 AFR AF: 0.0266 AC: 0.0266249 AN: 0.0266249

Gnomad4 AMR AF: 0.103 AC: 0.103405 AN: 0.103405

Gnomad4 ASJ AF: 0.133 AC: 0.132565 AN: 0.132565

Gnomad4 EAS AF: 0.00135 AC: 0.0013524 AN: 0.0013524

Gnomad4 SAS AF: 0.0909 AC: 0.0908714 AN: 0.0908714

Gnomad4 FIN AF: 0.126 AC: 0.126203 AN: 0.126203

Gnomad4 NFE AF: 0.146 AC: 0.145748 AN: 0.145748

Gnomad4 OTH AF: 0.0801 AC: 0.0800948 AN: 0.0800948

Alfa AF: 0.124 Hom.: 2638

Bravo AF: 0.0931

TwinsUK AF: 0.139 AC: 515

ALSPAC AF: 0.153 AC: 591

ESP6500AA AF: 0.0278 AC: 122

ESP6500EA AF: 0.149 AC: 1281

ExAC AF: 0.109 AC: 13205

Asia WGS AF: 0.0450 AC: 157 AN: 3476

EpiCase AF: 0.144

EpiControl AF: 0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.92
Eigen	Benign	0.064
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.43	N
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.64	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.26
Sift	Benign	0.036	D
Sift4G	Uncertain	0.025	D
Vest4		0.15
ClinPred		0.042	T
GERP RS		2.4
gMVP		0.65
Mutation Taster		=98/2	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

Publications

LitVar

Other links and lift over

dbSNP: rs41272110; hg19: chr6-161006172; COSMIC: COSV60315923; COSMIC: COSV60315923;