rs17603350

Variant names:

• chr2-11788297-C-T
• rs17603350
• NM_001349206.2:c.1644-90C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001349206.2(LPIN1):​c.1644-90C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 992,702 control chromosomes in the GnomAD database, including 580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (62 hom., cov: 32)
  • Exomes 𝑓: 0.030 (518 hom.)
• Consequence: LPIN1 NM_001349206.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.35
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-11788297-C-T is Benign according to our data. Variant chr2-11788297-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1187503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0248 (3776/152248) while in subpopulation NFE AF = 0.0399 (2713/68020). AF 95% confidence interval is 0.0386. There are 62 homozygotes in GnomAd4. There are 1744 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPIN1	NM_001349206.2	c.1644-90C>T		intron_variant	Intron 11 of 20	ENST00000674199.1	NP_001336135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPIN1	ENST00000674199.1	c.1644-90C>T		intron_variant	Intron 11 of 20		NM_001349206.2	ENSP00000501331.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3776 AN: 152130 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0321

GnomAD4 exome AF: 0.0304 AC: 25508 AN: 840454 Hom.: 518 AF XY: 0.0296 AC XY: 13087 AN XY: 442662

African (AFR) AF: 0.00661 AC: 142 AN: 21474

American (AMR) AF: 0.0186 AC: 788 AN: 42452

Ashkenazi Jewish (ASJ) AF: 0.0273 AC: 600 AN: 21938

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35992

South Asian (SAS) AF: 0.00748 AC: 544 AN: 72692

European-Finnish (FIN) AF: 0.0123 AC: 622 AN: 50742

Middle Eastern (MID) AF: 0.0229 AC: 104 AN: 4538

European-Non Finnish (NFE) AF: 0.0390 AC: 21469 AN: 551122

Other (OTH) AF: 0.0313 AC: 1238 AN: 39504

GnomAD4 genome AF: 0.0248 AC: 3776 AN: 152248 Hom.: 62 Cov.: 32 AF XY: 0.0234 AC XY: 1744 AN XY: 74444

African (AFR) AF: 0.00616 AC: 256 AN: 41540

American (AMR) AF: 0.0296 AC: 453 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4818

European-Finnish (FIN) AF: 0.0126 AC: 134 AN: 10604

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2713 AN: 68020

Other (OTH) AF: 0.0318 AC: 67 AN: 2110

Alfa AF: 0.0343 Hom.: 106

Bravo AF: 0.0254

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 11, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.055
DANN	Benign	0.69
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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: rs17603350; hg19: chr2-11928423;