rs1050800

Variant names:

• chr2-11825688-C-T
• rs1050800
• ENST00000404113.6:n.3163C>T

Variant summary

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

The ENST00000404113.6(LPIN1):​n.3163C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 152,518 control chromosomes in the GnomAD database, including 1,412 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 0.12 (1403 hom., cov: 32)
  • Exomes 𝑓: 0.19 (9 hom.)
• Consequence: LPIN1 ENST00000404113.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.83
• Publications: 15 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPIN1	NM_001349206.2	c.*897C>T		3_prime_UTR_variant	Exon 21 of 21	ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1	c.*897C>T		3_prime_UTR_variant	Exon 21 of 21		NM_001349206.2	ENSP00000501331.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18639 AN: 152028 Hom.: 1405 Cov.: 32

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.119

GnomAD4 exome AF: 0.188 AC: 70 AN: 372 Hom.: 9 Cov.: 0 AF XY: 0.192 AC XY: 43 AN XY: 224

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.190 AC: 70 AN: 368

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.122 AC: 18632 AN: 152146 Hom.: 1403 Cov.: 32 AF XY: 0.122 AC XY: 9083 AN XY: 74384

African (AFR) AF: 0.0377 AC: 1563 AN: 41512

American (AMR) AF: 0.141 AC: 2154 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 336 AN: 3470

East Asian (EAS) AF: 0.220 AC: 1137 AN: 5170

South Asian (SAS) AF: 0.111 AC: 536 AN: 4816

European-Finnish (FIN) AF: 0.162 AC: 1710 AN: 10570

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10728 AN: 68000

Other (OTH) AF: 0.116 AC: 245 AN: 2114

Alfa AF: 0.137 Hom.: 3045

Bravo AF: 0.118

Asia WGS AF: 0.138 AC: 481 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.1
DANN	Benign	0.79
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs1050800; hg19: chr2-11965814;