2-11713973-T-C

Variant names:

• chr2-11713973-T-C
• rs4668739
• NM_001261428.3:c.138+161T>C

Variant summary

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

The NM_001261428.3(LPIN1):​c.138+161T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 152,216 control chromosomes in the GnomAD database, including 14,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.40 (14191 hom., cov: 33)
• Consequence: LPIN1 NM_001261428.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0560
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Laboratory for Molecular Medicine, PanelApp Australia
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-11713973-T-C is Benign according to our data. Variant chr2-11713973-T-C is described in ClinVar as Benign. ClinVar VariationId is 683085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

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.138+161T>C		intron	N/A	NP_001248357.1	Q14693-7
	LPIN1	NM_001349207.2		c.81+36245T>C		intron	N/A	NP_001336136.1
	LPIN1	NM_001349208.2		c.138+161T>C		intron	N/A	NP_001336137.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000449576.6	TSL:2	c.138+161T>C		intron	N/A	ENSP00000397908.2	Q14693-7
	LPIN1	ENST00000852426.1		c.-10+161T>C		intron	N/A	ENSP00000522485.1
	LPIN1	ENST00000961822.1		c.-10+161T>C		intron	N/A	ENSP00000631881.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60433 AN: 152098 Hom.: 14190 Cov.: 33

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.437

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

GnomAD4 genome AF: 0.397 AC: 60440 AN: 152216 Hom.: 14191 Cov.: 33 AF XY: 0.400 AC XY: 29783 AN XY: 74422

African (AFR) AF: 0.133 AC: 5516 AN: 41552

American (AMR) AF: 0.484 AC: 7404 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1805 AN: 3468

East Asian (EAS) AF: 0.432 AC: 2233 AN: 5174

South Asian (SAS) AF: 0.553 AC: 2670 AN: 4830

European-Finnish (FIN) AF: 0.492 AC: 5208 AN: 10586

Middle Eastern (MID) AF: 0.442 AC: 129 AN: 292

European-Non Finnish (NFE) AF: 0.502 AC: 34112 AN: 67994

Other (OTH) AF: 0.440 AC: 929 AN: 2112

Alfa AF: 0.423 Hom.: 1999

Bravo AF: 0.381

Asia WGS AF: 0.506 AC: 1758 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.55
PhyloP100		-0.056
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: rs4668739; hg19: chr2-11854099;