rs35168378

chr16-870870-C-T

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.1091G>A(p.Arg364Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0268 in 1,608,236 control chromosomes in the GnomAD database, including 687 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R364W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (60 hom., cov: 33)
  • Exomes 𝑓: 0.027 (627 hom.)
• Consequence: LMF1 NM_022773.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.82

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055995286).
• BP6: Variant 16-870870-C-T is Benign according to our data. Variant chr16-870870-C-T is described in ClinVar as [Benign]. Clinvar id is 978327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-870870-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMF1	NM_022773.4	c.1091G>A	p.Arg364Gln	missense_variant	8/11	ENST00000262301.16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMF1	ENST00000262301.16	c.1091G>A	p.Arg364Gln	missense_variant	8/11	5	NM_022773.4	P1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4278 AN: 152170 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0306

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0245 AC: 5902 AN: 240702 Hom.: 112 AF XY: 0.0251 AC XY: 3310 AN XY: 131722

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0341

Gnomad EAS exome AF: 0.000396

Gnomad SAS exome AF: 0.0264

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0304

GnomAD4 exome AF: 0.0266 AC: 38788 AN: 1455948 Hom.: 627 Cov.: 32 AF XY: 0.0270 AC XY: 19525 AN XY: 724404

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0334

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0274

Gnomad4 OTH exome AF: 0.0285

GnomAD4 genome AF: 0.0281 AC: 4282 AN: 152288 Hom.: 60 Cov.: 33 AF XY: 0.0280 AC XY: 2088 AN XY: 74474

Gnomad4 AFR AF: 0.0352

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0308

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0278 Hom.: 82

Bravo AF: 0.0285

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.0365 AC: 155

ESP6500EA AF: 0.0251 AC: 213

ExAC AF: 0.0255 AC: 3077

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2019	This variant is associated with the following publications: (PMID: 31619059, 30037590, 33111339) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 26, 2019	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 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	0.19
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.089	T;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.080	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.98	D;.;.
Vest4		0.34
MPC		0.16
ClinPred		0.034	T
GERP RS		5.5
Varity_R		0.63
gMVP		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: rs35168378; hg19: chr16-920870; COSMIC: COSV51896016; COSMIC: COSV51896016;