2-11713787-G-T

Variant names:

• chr2-11713787-G-T
• rs4614906
• NM_001261428.3:c.113G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001261428.3(LPIN1):​c.113G>T​(p.Arg38Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000732 in 1,365,216 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: LPIN1 NM_001261428.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.11
• Publications: 10 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001261428.3. 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
	LPIN1	NM_001261428.3		c.113G>T	p.Arg38Leu	missense	Exon 2 of 22	NP_001248357.1	Q14693-7
	LPIN1	NM_001349208.2		c.113G>T	p.Arg38Leu	missense	Exon 2 of 21	NP_001336137.1
	LPIN1	NM_001349207.2		c.81+36059G>T		intron	N/A	NP_001336136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000449576.6	TSL:2	c.113G>T	p.Arg38Leu	missense	Exon 2 of 22	ENSP00000397908.2	Q14693-7
	LPIN1	ENST00000852426.1		c.-35G>T		5_prime_UTR	Exon 2 of 22	ENSP00000522485.1
	LPIN1	ENST00000961822.1		c.-35G>T		5_prime_UTR	Exon 2 of 21	ENSP00000631881.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000789 AC: 1 AN: 126740 AF XY: 0.0000144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1365216 Hom.: 0 Cov.: 27 AF XY: 0.00000148 AC XY: 1 AN XY: 674534

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31494

American (AMR) AF: 0.00 AC: 0 AN: 35422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25066

East Asian (EAS) AF: 0.00 AC: 0 AN: 35658

South Asian (SAS) AF: 0.00 AC: 0 AN: 78464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 9.41e-7 AC: 1 AN: 1062752

Other (OTH) AF: 0.00 AC: 0 AN: 57310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.47	D
PhyloP100		4.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.050	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Vest4		0.61
MutPred		0.44		Loss of MoRF binding (P = 0.0261)
MVP		0.76
MPC		0.42
ClinPred		0.66	D
GERP RS		4.9
gMVP		0.21
Mutation Taster		=84/16	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs4614906; hg19: chr2-11853913;