2-11787112-G-A

Variant names:

• chr2-11787112-G-A
• rs33997857
• NM_001349206.2:c.1588G>A

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.1588G>A​(p.Val530Met) variant causes a missense change. The variant allele was found at a frequency of 0.0174 in 1,613,934 control chromosomes in the GnomAD database, including 342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (34 hom., cov: 32)
  • Exomes 𝑓: 0.017 (308 hom.)
• Consequence: LPIN1 NM_001349206.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.37
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00783357).
• BP6: Variant 2-11787112-G-A is Benign according to our data. Variant chr2-11787112-G-A is described in ClinVar as Benign. ClinVar VariationId is 262583.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 = 0.0167 (2548/152302) while in subpopulation NFE AF = 0.024 (1635/68022). AF 95% confidence interval is 0.0231. There are 34 homozygotes in GnomAd4. There are 1227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349206.2. 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_001349206.2	MANE Select	c.1588G>A	p.Val530Met	missense	Exon 11 of 21	NP_001336135.1	Q14693-3
	LPIN1	NM_001261428.3		c.1735G>A	p.Val579Met	missense	Exon 12 of 22	NP_001248357.1	Q14693-7
	LPIN1	NM_001349207.2		c.1678G>A	p.Val560Met	missense	Exon 11 of 21	NP_001336136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000674199.1	MANE Select	c.1588G>A	p.Val530Met	missense	Exon 11 of 21	ENSP00000501331.1	Q14693-3
	LPIN1	ENST00000256720.6	TSL:1	c.1480G>A	p.Val494Met	missense	Exon 10 of 20	ENSP00000256720.2	Q14693-1
	LPIN1	ENST00000404113.6	TSL:1	n.1073G>A		non_coding_transcript_exon	Exon 6 of 16

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2549 AN: 152184 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0164 AC: 4122 AN: 251410 AF XY: 0.0165

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0209

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0175 AC: 25561 AN: 1461632 Hom.: 308 Cov.: 31 AF XY: 0.0174 AC XY: 12657 AN XY: 727144

African (AFR) AF: 0.00293 AC: 98 AN: 33478

American (AMR) AF: 0.0142 AC: 637 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 740 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00330 AC: 285 AN: 86254

European-Finnish (FIN) AF: 0.0326 AC: 1742 AN: 53414

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5768

European-Non Finnish (NFE) AF: 0.0188 AC: 20944 AN: 1111776

Other (OTH) AF: 0.0167 AC: 1006 AN: 60388

GnomAD4 genome AF: 0.0167 AC: 2548 AN: 152302 Hom.: 34 Cov.: 32 AF XY: 0.0165 AC XY: 1227 AN XY: 74466

African (AFR) AF: 0.00382 AC: 159 AN: 41570

American (AMR) AF: 0.0144 AC: 221 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4832

European-Finnish (FIN) AF: 0.0357 AC: 379 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1635 AN: 68022

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.0195 Hom.: 122

Bravo AF: 0.0135

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.0221 AC: 190

ExAC AF: 0.0157 AC: 1903

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0219

EpiControl AF: 0.0219

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Myoglobinuria, acute recurrent, autosomal recessive (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.19
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.032	D
Polyphen		0.24	B
Vest4		0.21
MPC		0.51
ClinPred		0.035	T
GERP RS		5.6
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.38
Mutation Taster		=298/2	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: rs33997857; hg19: chr2-11927238; COSMIC: COSV107217698; COSMIC: COSV107217698;