chr2-11791929-A-G

Variant names:

• chr2-11791929-A-G
• rs148499322
• NM_001349206.2:c.1729A>G

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.1729A>G​(p.Ile577Val) variant causes a missense change. The variant allele was found at a frequency of 0.00151 in 1,613,900 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (10 hom.)
• Consequence: LPIN1 NM_001349206.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.99
• Publications: 6 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=0.007960141).
• BP6: Variant 2-11791929-A-G is Benign according to our data. Variant chr2-11791929-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00183 (278/152326) while in subpopulation AMR AF = 0.00614 (94/15312). AF 95% confidence interval is 0.00514. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.1729A>G	p.Ile577Val	missense	Exon 13 of 21	NP_001336135.1	Q14693-3
	LPIN1	NM_001261428.3		c.1876A>G	p.Ile626Val	missense	Exon 14 of 22	NP_001248357.1	Q14693-7
	LPIN1	NM_001349207.2		c.1819A>G	p.Ile607Val	missense	Exon 13 of 21	NP_001336136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000674199.1	MANE Select	c.1729A>G	p.Ile577Val	missense	Exon 13 of 21	ENSP00000501331.1	Q14693-3
	LPIN1	ENST00000256720.6	TSL:1	c.1621A>G	p.Ile541Val	missense	Exon 12 of 20	ENSP00000256720.2	Q14693-1
	LPIN1	ENST00000404113.6	TSL:1	n.1214A>G		non_coding_transcript_exon	Exon 8 of 16

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152208 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00217 AC: 546 AN: 251358 AF XY: 0.00221

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00148 AC: 2165 AN: 1461574 Hom.: 10 Cov.: 32 AF XY: 0.00154 AC XY: 1122 AN XY: 727102

African (AFR) AF: 0.00111 AC: 37 AN: 33468

American (AMR) AF: 0.00400 AC: 179 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00712 AC: 186 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00217 AC: 187 AN: 86222

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53388

Middle Eastern (MID) AF: 0.0168 AC: 97 AN: 5762

European-Non Finnish (NFE) AF: 0.00116 AC: 1292 AN: 1111836

Other (OTH) AF: 0.00301 AC: 182 AN: 60386

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152326 Hom.: 1 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74498

African (AFR) AF: 0.000553 AC: 23 AN: 41576

American (AMR) AF: 0.00614 AC: 94 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68022

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00178 Hom.: 2

Bravo AF: 0.00233

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Myoglobinuria, acute recurrent, autosomal recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.18
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
Polyphen		0.017	B
Vest4		0.48
MVP		0.78
MPC		0.16
ClinPred		0.017	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.27
Mutation Taster		=97/3	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: rs148499322; hg19: chr2-11932055;