16-869982-G-C

Position:

• chr16-869982-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_022773.4(LMF1):​c.1317C>G​(p.Tyr439Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,952 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y439Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LMF1 NM_022773.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: -0.0970

Genes affected

LMF1 (HGNC:14154): (lipase maturation factor 1) Involved in triglyceride metabolic process. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum membrane. Implicated in familial lipase maturation factor 1 deficiency. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-869982-G-C is Pathogenic according to our data. Variant chr16-869982-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 792.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMF1	NM_022773.4	c.1317C>G	p.Tyr439Ter	stop_gained	9/11	ENST00000262301.16	NP_073610.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMF1	ENST00000262301.16	c.1317C>G	p.Tyr439Ter	stop_gained	9/11	5	NM_022773.4	ENSP00000262301	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460952 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726784

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: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Lipase deficiency, combined Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	GBinsight Genetic Testing by GB HealthWatch, Genben Lifesciences Corporation	May 27, 2020	Proband referred for clinical genetic testing presented with syndrome consistent with familial chylomicronemia syndrome with severe hypertriglyceridemia, low HDL-cholesterol and type 2 diabetes. Clinical genetic testing identified homozygosity for the Cys77Tyr (NM_178172.6:c.230G>A) genetic variant in the the germline. Phenotype segregated with genotype in family members. This variant introduces a premature stop codon, which can cause nonsense-mediated decay of the mutant protein. Péterfy et al (PMID: 17994020) identified this genetic variant in patients with severe hypertriglyceridemia and classified this variant as pathogenic for LMF1 deficiency. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2022

This sequence change creates a premature translational stop signal (p.Tyr439*) in the LMF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMF1 are known to be pathogenic (PMID: 17994020, 19820022, 22239554). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with combined lipase deficiency (PMID: 17994020). ClinVar contains an entry for this variant (Variation ID: 792). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LMF1 function (PMID: 17994020). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.020
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.64	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.76
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121909397; hg19: chr16-919982;