rs4614906

Variant names:

• chr2-11713787-G-A
• rs4614906
• NM_001261428.3:c.113G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-11713787-G-A
• chr2-11713787-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001261428.3(LPIN1):​c.113G>A​(p.Arg38Gln) variant causes a missense change. The variant allele was found at a frequency of 0.219 in 1,505,294 control chromosomes in the GnomAD database, including 38,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3224 hom., cov: 33)
  • Exomes 𝑓: 0.22 (35594 hom.)
• Consequence: LPIN1 NM_001261428.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 4.11
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Laboratory for Molecular Medicine, 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 (MetaRNN=0.0019290447).
• BP6: Variant 2-11713787-G-A is Benign according to our data. Variant chr2-11713787-G-A is described in ClinVar as Benign. ClinVar VariationId is 403045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001261428.3. 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_001261428.3		c.113G>A	p.Arg38Gln	missense	Exon 2 of 22	NP_001248357.1	Q14693-7
	LPIN1	NM_001349208.2		c.113G>A	p.Arg38Gln	missense	Exon 2 of 21	NP_001336137.1
	LPIN1	NM_001349207.2		c.81+36059G>A		intron	N/A	NP_001336136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPIN1	ENST00000449576.6	TSL:2	c.113G>A	p.Arg38Gln	missense	Exon 2 of 22	ENSP00000397908.2	Q14693-7
	LPIN1	ENST00000852426.1		c.-35G>A		5_prime_UTR	Exon 2 of 22	ENSP00000522485.1
	LPIN1	ENST00000961822.1		c.-35G>A		5_prime_UTR	Exon 2 of 21	ENSP00000631881.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27583 AN: 152004 Hom.: 3221 Cov.: 33

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.227 AC: 28792 AN: 126740 AF XY: 0.229

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.223 AC: 301780 AN: 1353172 Hom.: 35594 Cov.: 27 AF XY: 0.225 AC XY: 150184 AN XY: 668858

African (AFR) AF: 0.0361 AC: 1135 AN: 31454

American (AMR) AF: 0.279 AC: 9815 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 4879 AN: 24964

East Asian (EAS) AF: 0.196 AC: 6987 AN: 35608

South Asian (SAS) AF: 0.257 AC: 20011 AN: 77922

European-Finnish (FIN) AF: 0.269 AC: 8947 AN: 33308

Middle Eastern (MID) AF: 0.223 AC: 1252 AN: 5610

European-Non Finnish (NFE) AF: 0.225 AC: 236724 AN: 1052212

Other (OTH) AF: 0.211 AC: 12030 AN: 56890

GnomAD4 genome AF: 0.181 AC: 27582 AN: 152122 Hom.: 3224 Cov.: 33 AF XY: 0.185 AC XY: 13775 AN XY: 74356

African (AFR) AF: 0.0432 AC: 1793 AN: 41500

American (AMR) AF: 0.236 AC: 3612 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 714 AN: 3470

East Asian (EAS) AF: 0.173 AC: 892 AN: 5170

South Asian (SAS) AF: 0.261 AC: 1257 AN: 4824

European-Finnish (FIN) AF: 0.276 AC: 2914 AN: 10564

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15752 AN: 67984

Other (OTH) AF: 0.163 AC: 345 AN: 2114

Alfa AF: 0.220 Hom.: 4715

Bravo AF: 0.172

TwinsUK AF: 0.231 AC: 856

ALSPAC AF: 0.220 AC: 846

ExAC AF: 0.209 AC: 2860

Asia WGS AF: 0.173 AC: 600 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
1	-	-	Hyperchloremia (1)
-	-	1	LPIN1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.2	T
PhyloP100		4.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Vest4		0.15
MPC		0.22
ClinPred		0.016	T
GERP RS		4.9
gMVP		0.11
Mutation Taster		=94/6	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4614906; hg19: chr2-11853913; COSMIC: COSV71938074;