16-854599-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022773.4(LMF1):c.1637C>G(p.Pro546Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000756 in 1,454,520 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 (★). Synonymous variant affecting the same amino acid position (i.e. P546P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: LMF1 NM_022773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.28

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMF1	NM_022773.4	c.1637C>G	p.Pro546Arg	missense_variant	11/11	ENST00000262301.16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMF1	ENST00000262301.16	c.1637C>G	p.Pro546Arg	missense_variant	11/11	5	NM_022773.4	P1
	ENST00000655150.1	n.632-6433G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000129 AC: 3 AN: 232746 Hom.: 0 AF XY: 0.0000157 AC XY: 2 AN XY: 127546

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000289

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1454520 Hom.: 0 Cov.: 31 AF XY: 0.00000968 AC XY: 7 AN XY: 723190

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: 0.00000991

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.1637C>G (p.P546R) alteration is located in exon 11 (coding exon 11) of the LMF1 gene. This alteration results from a C to G substitution at nucleotide position 1637, causing the proline (P) at amino acid position 546 to be replaced by an arginine (R). 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	Benign	0.30
BayesDel_addAF	Benign	-0.0023	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.74
MutPred		0.54		Gain of MoRF binding (P = 8e-04);.;.;
MVP		0.44
MPC		0.16
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.70
gMVP		0.69

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: rs199843015; hg19: chr16-904599;