rs149564563

chr2-11782200-GTCT-Gchr2-11782200-GTCT-GTCTTCT

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PP3_Moderate BP3 BP6_Very_Strong BS1 BS2

The NM_001349206.2(LPIN1):c.964_966del(p.Ser322del) variant causes a inframe deletion, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,014 control chromosomes in the GnomAD database, including 44 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (20 hom.)
• Consequence: LPIN1 NM_001349206.2 inframe_deletion, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.10

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP3: Nonframeshift variant in repetitive region in NM_001349206.2
• BP6: Variant 2-11782200-GTCT-G is Benign according to our data. Variant chr2-11782200-GTCT-G is described in ClinVar as [Likely_benign]. Clinvar id is 262597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (1556/152188) while in subpopulation AFR AF= 0.0352 (1462/41502). AF 95% confidence interval is 0.0337. There are 24 homozygotes in gnomad4. There are 728 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN1	NM_001349206.2	c.964_966del	p.Ser322del	inframe_deletion, splice_region_variant	8/21	ENST00000674199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN1	ENST00000674199.1	c.964_966del	p.Ser322del	inframe_deletion, splice_region_variant	8/21		NM_001349206.2	P4

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1554 AN: 152070 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00238 AC: 595 AN: 250492 Hom.: 5 AF XY: 0.00181 AC XY: 246 AN XY: 135590

Gnomad AFR exome AF: 0.0339

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00103 AC: 1504 AN: 1460826 Hom.: 20 AF XY: 0.000890 AC XY: 647 AN XY: 726800

Gnomad4 AFR exome AF: 0.0387

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.0102 AC: 1556 AN: 152188 Hom.: 24 Cov.: 32 AF XY: 0.00978 AC XY: 728 AN XY: 74400

Gnomad4 AFR AF: 0.0352

Gnomad4 AMR AF: 0.00478

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00147 Hom.: 2

Bravo AF: 0.0122

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2018	This variant is associated with the following publications: (PMID: 22481384) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 13, 2022

- -

Acute Recurrent Myoglobinuria Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: 4
DS_AL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs149564563; hg19: chr2-11922326;