rs249

Variant names:

• chr8-19953495-T-C
• rs249
• NM_000237.3:c.541+74T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-19953495-T-C
• chr8-19953495-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000237.3(LPL):​c.541+74T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 1,103,958 control chromosomes in the GnomAD database, including 3,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (710 hom., cov: 33)
  • Exomes 𝑓: 0.078 (3043 hom.)
• Consequence: LPL NM_000237.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0110
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• familial lipoprotein lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hyperlipidemia, familial combined, LPL related

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-19953495-T-C is Benign according to our data. Variant chr8-19953495-T-C is described in ClinVar as Benign. ClinVar VariationId is 1237990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.541+74T>C		intron_variant	Intron 4 of 9	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.541+74T>C		intron_variant	Intron 4 of 9		NM_000237.3	ENSP00000497642.1
LPL	ENST00000520959.5	c.313+74T>C		intron_variant	Intron 4 of 4	4		ENSP00000428496.1

Frequencies

GnomAD3 genomes AF: 0.0911 AC: 13416 AN: 147252 Hom.: 711 Cov.: 33

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0302

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.0664

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.100

Gnomad NFE AF: 0.0806

Gnomad OTH AF: 0.0799

GnomAD4 exome AF: 0.0775 AC: 74180 AN: 956606 Hom.: 3043 AF XY: 0.0784 AC XY: 38890 AN XY: 496098

African (AFR) AF: 0.138 AC: 3340 AN: 24134

American (AMR) AF: 0.0359 AC: 1519 AN: 42364

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 957 AN: 22524

East Asian (EAS) AF: 0.0704 AC: 2598 AN: 36906

South Asian (SAS) AF: 0.101 AC: 7532 AN: 74922

European-Finnish (FIN) AF: 0.0422 AC: 1998 AN: 47372

Middle Eastern (MID) AF: 0.0677 AC: 324 AN: 4784

European-Non Finnish (NFE) AF: 0.0799 AC: 52756 AN: 660048

Other (OTH) AF: 0.0725 AC: 3156 AN: 43552

GnomAD4 genome AF: 0.0910 AC: 13413 AN: 147352 Hom.: 710 Cov.: 33 AF XY: 0.0893 AC XY: 6434 AN XY: 72074

African (AFR) AF: 0.145 AC: 5534 AN: 38138

American (AMR) AF: 0.0561 AC: 829 AN: 14776

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 137 AN: 3396

East Asian (EAS) AF: 0.0661 AC: 336 AN: 5082

South Asian (SAS) AF: 0.113 AC: 537 AN: 4732

European-Finnish (FIN) AF: 0.0368 AC: 386 AN: 10500

Middle Eastern (MID) AF: 0.100 AC: 29 AN: 290

European-Non Finnish (NFE) AF: 0.0805 AC: 5436 AN: 67486

Other (OTH) AF: 0.0787 AC: 162 AN: 2058

Alfa AF: 0.0856 Hom.: 152

Bravo AF: 0.0882

Asia WGS AF: 0.0880 AC: 305 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.6
DANN	Benign	0.59
PhyloP100		-0.011

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: rs249; hg19: chr8-19811006;