19-42401940-C-A

Variant names:

• chr19-42401940-C-A
• rs766817317
• NM_005357.4:c.3103G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_005357.4(LIPE):​c.3103G>T​(p.Glu1035*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000713 in 1,403,302 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: LIPE NM_005357.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.32

Genes affected

LIPE (HGNC:6621): (lipase E, hormone sensitive type) The protein encoded by this gene has a long and a short form, generated by use of alternative translational start codons. The long form is expressed in steroidogenic tissues such as testis, where it converts cholesteryl esters to free cholesterol for steroid hormone production. The short form is expressed in adipose tissue, among others, where it hydrolyzes stored triglycerides to free fatty acids. [provided by RefSeq, Jul 2008]

LIPE-AS1 (HGNC:48589): (LIPE antisense RNA 1)

LOC101930071 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0396 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-42401940-C-A is Pathogenic according to our data. Variant chr19-42401940-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522594.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPE	NM_005357.4	c.3103G>T	p.Glu1035*	stop_gained	Exon 10 of 10	ENST00000244289.9	NP_005348.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPE	ENST00000244289.9	c.3103G>T	p.Glu1035*	stop_gained	Exon 10 of 10	1	NM_005357.4	ENSP00000244289.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1403302 Hom.: 0 Cov.: 36 AF XY: 0.00000144 AC XY: 1 AN XY: 693944

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: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 10, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 42 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 27862896) -

LIPE-related familial partial lipodystrophy Pathogenic:1

Jan 19, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.89	D
Vest4		0.81
GERP RS		4.3

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: rs766817317; hg19: chr19-42906092;