8-19951924-G-A

Position:

chr8-19951924-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000237.3(LPL):c.405G>A(p.Val135Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,614,046 control chromosomes in the GnomAD database, including 1,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 347 hom., cov: 32)

Exomes 𝑓: 0.032 ( 998 hom. )

Consequence

LPL
NM_000237.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.537

Variant links:

Genes affected

LPL (HGNC:6677): (lipoprotein lipase) LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism. [provided by RefSeq, Jul 2008]

LPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 8-19951924-G-A is Benign according to our data. Variant chr8-19951924-G-A is described in ClinVar as [Benign]. Clinvar id is 362407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19951924-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.537 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.405G>A	p.Val135Val	synonymous_variant	3/10	ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.405G>A	p.Val135Val	synonymous_variant	3/10		NM_000237.3	ENSP00000497642.1	P06858
LPL	ENST00000520959.5 linkuse as main transcript	c.177G>A	p.Val59Val	synonymous_variant	3/5	4		ENSP00000428496.1	E7EW14
LPL	ENST00000524029.5 linkuse as main transcript	c.*16G>A		downstream_gene_variant		4		ENSP00000428237.1	E5RJI0

Frequencies

GnomAD3 genomes

AF:

0.0546

AC:

8298

AN:

152076

Hom.:

346

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0420

Gnomad ASJ

AF:

0.0657

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0331

Gnomad OTH

AF:

0.0445

GnomAD3 exomes

AF:

0.0332

AC:

8353

AN:

251430

Hom.:

225

AF XY:

0.0313

AC XY:

4247

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.0252

Gnomad ASJ exome

AF:

0.0661

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0103

Gnomad FIN exome

AF:

0.0290

Gnomad NFE exome

AF:

0.0334

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0320

AC:

46818

AN:

1461852

Hom.:

998

Cov.:

AF XY:

0.0316

AC XY:

22997

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.0262

Gnomad4 ASJ exome

AF:

0.0631

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0107

Gnomad4 FIN exome

AF:

0.0266

Gnomad4 NFE exome

AF:

0.0317

Gnomad4 OTH exome

AF:

0.0367

GnomAD4 genome

AF:

0.0546

AC:

8317

AN:

152194

Hom.:

347

Cov.:

AF XY:

0.0535

AC XY:

3977

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.111

Gnomad4 AMR

AF:

0.0420

Gnomad4 ASJ

AF:

0.0657

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00912

Gnomad4 FIN

AF:

0.0347

Gnomad4 NFE

AF:

0.0331

Gnomad4 OTH

AF:

0.0441

Alfa

AF:

0.0418

Hom.:

219

Bravo

AF:

0.0577

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0388

EpiControl

AF:

0.0406

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2017	Variant summary: The LPL c.405G>A (p.Val135Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SF2/ASF. This variant was found in 4195/121380 control chromosomes (117 homozygotes) from ExAC, predominantly observed in the African subpopulation at a frequency of 0.116997 (1217/10402). This frequency is about 35 times the estimated maximal expected allele frequency of a pathogenic LPL variant (0.0033541), thus this is a benign polymorphism found primarily in the populations of African origin. This variant was also not associated with Type 2 diabetes or lowered HDL-C levels in a case-control study from India (Ayyappa_2017). One clinical laboratory (via ClinVar) has classified this variant as likely benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hyperlipoproteinemia, type I

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dystrophin deficiency

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.0

DANN

Benign

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over