NM_005357.4:c.3188C>G

Variant names:

• chr19-42401855-G-C
• rs745859081
• NM_005357.4:c.3188C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005357.4(LIPE):​c.3188C>G​(p.Thr1063Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 131,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIPE NM_005357.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.29
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0627743).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005357.4. 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
	LIPE	NM_005357.4	MANE Select	c.3188C>G	p.Thr1063Arg	missense	Exon 10 of 10	NP_005348.2
	LIPE	NM_001416100.1		c.2438C>G	p.Thr813Arg	missense	Exon 10 of 10	NP_001403029.1
	LIPE	NM_001416101.1		c.2423C>G	p.Thr808Arg	missense	Exon 10 of 10	NP_001403030.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPE	ENST00000244289.9	TSL:1 MANE Select	c.3188C>G	p.Thr1063Arg	missense	Exon 10 of 10	ENSP00000244289.3	Q05469-1
	LIPE-AS1	ENST00000594624.8	TSL:1	n.105+4631G>C		intron	N/A
	LIPE	ENST00000599918.2	TSL:5	c.3212C>G	p.Thr1071Arg	missense	Exon 10 of 10	ENSP00000472218.2	M0R201

Frequencies

GnomAD3 genomes AF: 0.0000228 AC: 3 AN: 131366 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000516

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 86586 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000324 AC: 10 AN: 308442 Hom.: 0 Cov.: 7 AF XY: 0.0000307 AC XY: 5 AN XY: 162978

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6154

American (AMR) AF: 0.00 AC: 0 AN: 13768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8120

East Asian (EAS) AF: 0.000187 AC: 1 AN: 5358

South Asian (SAS) AF: 0.0000234 AC: 1 AN: 42664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1068

European-Non Finnish (NFE) AF: 0.0000394 AC: 8 AN: 203010

Other (OTH) AF: 0.00 AC: 0 AN: 12920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00121592), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000228 AC: 3 AN: 131464 Hom.: 0 Cov.: 31 AF XY: 0.0000315 AC XY: 2 AN XY: 63406

African (AFR) AF: 0.00 AC: 0 AN: 36218

American (AMR) AF: 0.00 AC: 0 AN: 13340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3146

East Asian (EAS) AF: 0.000517 AC: 2 AN: 3870

South Asian (SAS) AF: 0.00 AC: 0 AN: 3356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000164 AC: 1 AN: 60812

Other (OTH) AF: 0.00 AC: 0 AN: 1832

Alfa AF: 0.0000332 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.60
DANN	Benign	0.83
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.050
Sift	Benign	0.81	T
Sift4G	Uncertain	0.016	D
Polyphen		0.96	D
Vest4		0.060
MutPred		0.17		Loss of glycosylation at T1063 (P = 0.0134)
MVP		0.48
MPC		0.35
ClinPred		0.15	T
GERP RS		-0.64
Varity_R		0.049
gMVP		0.20
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: rs745859081; hg19: chr19-42906007;