rs3751667

Variant names:

• chr16-954554-C-T
• rs3751667
• NM_022773.4:c.306G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022773.4(LMF1):​c.306G>A​(p.Thr102Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,612,686 control chromosomes in the GnomAD database, including 56,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7115 hom., cov: 33)
  • Exomes 𝑓: 0.25 (48952 hom.)
• Consequence: LMF1 NM_022773.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.13
• Publications: 54 publications found

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 Gene-Disease associations (from GenCC):

• lipase deficiency, combined

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-954554-C-T is Benign according to our data. Variant chr16-954554-C-T is described in ClinVar as Benign. ClinVar VariationId is 1246959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMF1	NM_022773.4	c.306G>A	p.Thr102Thr	synonymous_variant	Exon 2 of 11	ENST00000262301.16	NP_073610.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMF1	ENST00000262301.16	c.306G>A	p.Thr102Thr	synonymous_variant	Exon 2 of 11	5	NM_022773.4	ENSP00000262301.12

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43957 AN: 152038 Hom.: 7102 Cov.: 33

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.277 AC: 68629 AN: 247618 AF XY: 0.280

Gnomad AFR exome AF: 0.406

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.407

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.250 AC: 365474 AN: 1460530 Hom.: 48952 Cov.: 37 AF XY: 0.255 AC XY: 184971 AN XY: 726506

African (AFR) AF: 0.415 AC: 13882 AN: 33460

American (AMR) AF: 0.289 AC: 12895 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5828 AN: 26130

East Asian (EAS) AF: 0.392 AC: 15541 AN: 39682

South Asian (SAS) AF: 0.421 AC: 36341 AN: 86220

European-Finnish (FIN) AF: 0.152 AC: 7995 AN: 52768

Middle Eastern (MID) AF: 0.259 AC: 1494 AN: 5768

European-Non Finnish (NFE) AF: 0.230 AC: 255634 AN: 1111542

Other (OTH) AF: 0.263 AC: 15864 AN: 60350

GnomAD4 genome AF: 0.289 AC: 44011 AN: 152156 Hom.: 7115 Cov.: 33 AF XY: 0.287 AC XY: 21343 AN XY: 74398

African (AFR) AF: 0.402 AC: 16674 AN: 41484

American (AMR) AF: 0.278 AC: 4256 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 817 AN: 3468

East Asian (EAS) AF: 0.406 AC: 2100 AN: 5174

South Asian (SAS) AF: 0.437 AC: 2106 AN: 4816

European-Finnish (FIN) AF: 0.130 AC: 1376 AN: 10602

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15743 AN: 68006

Other (OTH) AF: 0.276 AC: 583 AN: 2110

Alfa AF: 0.253 Hom.: 16167

Bravo AF: 0.301

Asia WGS AF: 0.414 AC: 1441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 03, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.64
DANN	Benign	0.29
PhyloP100		-1.1
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3751667; hg19: chr16-1004554; COSMIC: COSV51897207;