rs4984948

chr16-854551-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022773.4(LMF1):c.1685C>G(p.Pro562Arg) variant causes a missense change. The variant allele was found at a frequency of 0.02 in 1,608,040 control chromosomes in the GnomAD database, including 1,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.026 (225 hom., cov: 33)
  • Exomes 𝑓: 0.019 (1252 hom.)
• Consequence: LMF1 NM_022773.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.50

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017978847).
• BP6: Variant 16-854551-G-C is Benign according to our data. Variant chr16-854551-G-C is described in ClinVar as [Benign]. Clinvar id is 1277320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMF1	NM_022773.4	c.1685C>G	p.Pro562Arg	missense_variant	11/11	ENST00000262301.16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMF1	ENST00000262301.16	c.1685C>G	p.Pro562Arg	missense_variant	11/11	5	NM_022773.4	P1
	ENST00000655150.1	n.632-6481G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3977 AN: 152166 Hom.: 222 Cov.: 33

Gnomad AFR AF: 0.00799

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0524

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00713

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0468 AC: 11050 AN: 236352 Hom.: 754 AF XY: 0.0412 AC XY: 5357 AN XY: 129908

Gnomad AFR exome AF: 0.00605

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.00747

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.0502

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.0329

GnomAD4 exome AF: 0.0193 AC: 28119 AN: 1455756 Hom.: 1252 Cov.: 31 AF XY: 0.0197 AC XY: 14250 AN XY: 724096

Gnomad4 AFR exome AF: 0.00667

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.00683

Gnomad4 EAS exome AF: 0.129

Gnomad4 SAS exome AF: 0.0517

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00807

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0262 AC: 3984 AN: 152284 Hom.: 225 Cov.: 33 AF XY: 0.0300 AC XY: 2231 AN XY: 74452

Gnomad4 AFR AF: 0.00796

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.0523

Gnomad4 FIN AF: 0.0130

Gnomad4 NFE AF: 0.00713

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.00983 Hom.: 5

Bravo AF: 0.0332

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00615 AC: 24

ESP6500EA AF: 0.00910 AC: 75

ExAC AF: 0.0371 AC: 4454

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	This variant is associated with the following publications: (PMID: 27108409, 22239554, 25817768, 30420299) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.9	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.25
Sift	Benign	0.084	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.75	P;.;.
Vest4		0.19
MPC		0.10
ClinPred		0.032	T
GERP RS		4.4
Varity_R		0.30
gMVP		0.62

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: rs4984948; hg19: chr16-904551; COSMIC: COSV51894821;