2-11791929-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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:5
• Conservation: PhyloP100: 3.99

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 -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 [Likely_benign]. Clinvar id is 262585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-11791929-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPIN1	NM_001349206.2	c.1729A>G	p.Ile577Val	missense_variant	13/21	ENST00000674199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPIN1	ENST00000674199.1	c.1729A>G	p.Ile577Val	missense_variant	13/21		NM_001349206.2	P4

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

GnomAD3 exomes AF: 0.00217 AC: 546 AN: 251358 Hom.: 4 AF XY: 0.00221 AC XY: 300 AN XY: 135838

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 SAS exome AF: 0.00196

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

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00712

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00217

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00116

Gnomad4 OTH exome AF: 0.00301

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

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00172 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

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LPIN1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	This variant is associated with the following publications: (PMID: 22481384) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Myoglobinuria, acute recurrent, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D;D;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0080	T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	0.97	D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.46	N;N;.;N;N
REVEL	Benign	0.18
Sift	Benign	0.28	T;T;.;T;T
Sift4G	Benign	0.27	T;T;T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs148499322; hg19: chr2-11932055;