chr20-41347616-C-A

Position:

• chr20-41347616-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022896.3(LPIN3):​c.257C>A​(p.Ala86Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LPIN3 NM_022896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06

Genes affected

LPIN3 (HGNC:14451): (lipin 3) The protein encoded by this gene is a member of the lipin family of proteins, and all family members share strong homology in their C-terminal region. This protein is thought to form hetero-oligomers with other lipin family members, while one family member, lipin 1, can also form homo-oligomers. This protein contains conserved motifs for phosphatidate phosphatase 1 (PAP1) activity as well as a domain that interacts with a transcriptional co-activator. Lipin complexes act in the cytoplasm to catalyze the dephosphorylation of phosphatidic acid to produce diacylglycerol, which is the precursor of both triglycerides and phospholipids. Lipin complexes are also thought to regulate gene expression as transcriptional co-activators in the nucleus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPIN3	NM_022896.3	c.257C>A	p.Ala86Asp	missense_variant	3/20	ENST00000373257.8	NP_075047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPIN3	ENST00000373257.8	c.257C>A	p.Ala86Asp	missense_variant	3/20	5	NM_022896.3	ENSP00000362354	A2
LPIN3	ENST00000632009.1	c.257C>A	p.Ala86Asp	missense_variant	3/20	1		ENSP00000487971	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.257C>A (p.A86D) alteration is located in exon 3 (coding exon 2) of the LPIN3 gene. This alteration results from a C to A substitution at nucleotide position 257, causing the alanine (A) at amino acid position 86 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.85		Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);
MVP		0.95
MPC		0.77
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.93

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: rs2045830532; hg19: chr20-39976256;