rs4669778

Variant names:

• chr2-11743854-T-C
• rs4669778
• ENST00000396098.5:c.9+2426T>C

Variant summary

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

The ENST00000396098.5(LPIN1):​c.9+2426T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 151,988 control chromosomes in the GnomAD database, including 22,765 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (22765 hom., cov: 32)
• Consequence: LPIN1 ENST00000396098.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.508
• Publications: 6 publications found

Genes affected

LPIN1 (HGNC:13345): (lipin 1) This gene encodes a magnesium-ion-dependent phosphatidic acid phosphohydrolase enzyme that catalyzes the penultimate step in triglyceride synthesis including the dephosphorylation of phosphatidic acid to yield diacylglycerol. Expression of this gene is required for adipocyte differentiation and it also functions as a nuclear transcriptional coactivator with some peroxisome proliferator-activated receptors to modulate expression of other genes involved in lipid metabolism. Mutations in this gene are associated with metabolic syndrome, type 2 diabetes, acute recurrent rhabdomyolysis, and autosomal recessive acute recurrent myoglobinuria (ARARM). This gene is also a candidate for several human lipodystrophy syndromes. [provided by RefSeq, Mar 2017]

LPIN1 Gene-Disease associations (from GenCC):

• myoglobinuria, acute recurrent, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124907735 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124907735	XR_007086220.1	n.1606A>G		non_coding_transcript_exon_variant	Exon 1 of 2
LPIN1	NM_001261428.3	c.139-21679T>C		intron_variant	Intron 2 of 21		NP_001248357.1
LPIN1	NM_001349207.2	c.82-21679T>C		intron_variant	Intron 1 of 20		NP_001336136.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000396098.5	c.9+2426T>C		intron_variant	Intron 2 of 9	1		ENSP00000379405.1
LPIN1	ENST00000449576.6	c.139-21679T>C		intron_variant	Intron 2 of 21	2		ENSP00000397908.2
LPIN1	ENST00000396097.5	c.9+2426T>C		intron_variant	Intron 2 of 21	5		ENSP00000379404.2

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80275 AN: 151870 Hom.: 22740 Cov.: 32

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.498

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.529 AC: 80354 AN: 151988 Hom.: 22765 Cov.: 32 AF XY: 0.521 AC XY: 38691 AN XY: 74308

African (AFR) AF: 0.745 AC: 30861 AN: 41446

American (AMR) AF: 0.464 AC: 7089 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3470

East Asian (EAS) AF: 0.236 AC: 1218 AN: 5152

South Asian (SAS) AF: 0.389 AC: 1877 AN: 4820

European-Finnish (FIN) AF: 0.428 AC: 4530 AN: 10582

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.464 AC: 31551 AN: 67936

Other (OTH) AF: 0.494 AC: 1041 AN: 2106

Alfa AF: 0.481 Hom.: 10770

Bravo AF: 0.540

Asia WGS AF: 0.320 AC: 1113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.6
DANN	Benign	0.74
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4669778; hg19: chr2-11883980;