chr16-933990-C-T

Variant names:

• chr16-933990-C-T
• rs72759474
• NM_022773.4:c.514+254G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_001352018.2(LMF1):​c.115+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,466,868 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: LMF1 NM_001352018.2 splice_donor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.434

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]

LMF1-AS1 (HGNC:50469): (LMF1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BP6: Variant 16-933990-C-T is Benign according to our data. Variant chr16-933990-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2634249.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0018 (274/152352) while in subpopulation NFE AF= 0.00316 (215/68028). AF 95% confidence interval is 0.00281. There are 0 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMF1	NM_022773.4	c.514+254G>A		intron_variant	Intron 3 of 10	ENST00000262301.16	NP_073610.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMF1	ENST00000262301.16	c.514+254G>A		intron_variant	Intron 3 of 10	5	NM_022773.4	ENSP00000262301.12

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152234 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00150 AC: 192 AN: 128326 Hom.: 1 AF XY: 0.00142 AC XY: 100 AN XY: 70180

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.000944

Gnomad ASJ exome AF: 0.000124

Gnomad EAS exome AF: 0.000191

Gnomad SAS exome AF: 0.0000446

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00312

Gnomad OTH exome AF: 0.00226

GnomAD4 exome AF: 0.00246 AC: 3235 AN: 1314516 Hom.: 5 Cov.: 29 AF XY: 0.00247 AC XY: 1595 AN XY: 646762

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000968

Gnomad4 SAS exome AF: 0.0000515

Gnomad4 FIN exome AF: 0.000189

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152352 Hom.: 0 Cov.: 34 AF XY: 0.00176 AC XY: 131 AN XY: 74502

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00248 Hom.: 0

Bravo AF: 0.00183

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lipase deficiency, combined Uncertain:1

Oct 20, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

LMF1-related disorder Uncertain:1

Jul 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LMF1 c.115+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is predicted to disrupt a canonical splice donor site based on prediction algorithms; however, such predictions are not equivalent to functional evidence (Alamut Visual Plus v1.6.1). In the primary transcript listed in the Human Gene Mutation Database (HGMD; https://www.hgmd.cf.ac.uk/), this variant is deep intronic (NM_022773.4, c.514+254G>A). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.33% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-983990-C-T), which may be too frequent to be an unreported primary cause of disease. We suspect that this variant could be benign (based on observed minor allele frequency), but at this time interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.4
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72759474; hg19: chr16-983990;