rs1121923

Variant names:

• chr8-19951924-G-A
• rs1121923
• NM_000237.3:c.405G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-19951924-G-A
• chr8-19951924-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.537
• Publications: 25 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 -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 VariationId is 362407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000237.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	NM_000237.3	MANE Select	c.405G>A	p.Val135Val	synonymous	Exon 3 of 10	NP_000228.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	ENST00000650287.1	MANE Select	c.405G>A	p.Val135Val	synonymous	Exon 3 of 10	ENSP00000497642.1
	LPL	ENST00000965928.1		c.405G>A	p.Val135Val	synonymous	Exon 5 of 12	ENSP00000635987.1
	LPL	ENST00000965929.1		c.405G>A	p.Val135Val	synonymous	Exon 3 of 10	ENSP00000635988.1

Frequencies

GnomAD3 genomes AF: 0.0546 AC: 8298 AN: 152076 Hom.: 346 Cov.: 32

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

GnomAD2 exomes AF: 0.0332 AC: 8353 AN: 251430 AF XY: 0.0313

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 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.: 31 AF XY: 0.0316 AC XY: 22997 AN XY: 727228

African (AFR) AF: 0.116 AC: 3877 AN: 33478

American (AMR) AF: 0.0262 AC: 1170 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 1649 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0107 AC: 926 AN: 86256

European-Finnish (FIN) AF: 0.0266 AC: 1421 AN: 53420

Middle Eastern (MID) AF: 0.0621 AC: 358 AN: 5768

European-Non Finnish (NFE) AF: 0.0317 AC: 35198 AN: 1111974

Other (OTH) AF: 0.0367 AC: 2219 AN: 60396

GnomAD4 genome AF: 0.0546 AC: 8317 AN: 152194 Hom.: 347 Cov.: 32 AF XY: 0.0535 AC XY: 3977 AN XY: 74390

African (AFR) AF: 0.111 AC: 4621 AN: 41518

American (AMR) AF: 0.0420 AC: 641 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4824

European-Finnish (FIN) AF: 0.0347 AC: 368 AN: 10592

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0331 AC: 2251 AN: 68024

Other (OTH) AF: 0.0441 AC: 93 AN: 2110

Alfa AF: 0.0435 Hom.: 312

Bravo AF: 0.0577

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0388

EpiControl AF: 0.0406

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dystrophin deficiency (1)
-	-	1	Hyperlipoproteinemia, type I (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.0
DANN	Benign	0.59
PhyloP100		-0.54

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: rs1121923; hg19: chr8-19809435; COSMIC: COSV60932154; COSMIC: COSV60932154;