16-870870-C-T

Variant names:

• chr16-870870-C-T
• rs35168378
• NM_022773.4:c.1091G>A

Variant summary

Our verdict is Benign. The variant received -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 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:7
• Conservation: PhyloP100: 5.82
• Publications: 22 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 978327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022773.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMF1	NM_022773.4	MANE Select	c.1091G>A	p.Arg364Gln	missense	Exon 8 of 11	NP_073610.2	Q96S06-1
	LMF1	NM_001352020.1		c.1091G>A	p.Arg364Gln	missense	Exon 8 of 11	NP_001338949.1
	LMF1	NM_001352019.2		c.764G>A	p.Arg255Gln	missense	Exon 8 of 11	NP_001338948.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMF1	ENST00000262301.16	TSL:5 MANE Select	c.1091G>A	p.Arg364Gln	missense	Exon 8 of 11	ENSP00000262301.12	Q96S06-1
	LMF1	ENST00000963976.1		c.1091G>A	p.Arg364Gln	missense	Exon 8 of 12	ENSP00000634035.1
	LMF1	ENST00000568897.5	TSL:5	c.440G>A	p.Arg147Gln	missense	Exon 7 of 10	ENSP00000458135.1	H3BVI4

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

GnomAD2 exomes AF: 0.0245 AC: 5902 AN: 240702 AF XY: 0.0251

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 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

African (AFR) AF: 0.0392 AC: 1312 AN: 33460

American (AMR) AF: 0.0175 AC: 779 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 871 AN: 26062

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39668

South Asian (SAS) AF: 0.0281 AC: 2422 AN: 86164

European-Finnish (FIN) AF: 0.0194 AC: 945 AN: 48732

Middle Eastern (MID) AF: 0.0557 AC: 321 AN: 5762

European-Non Finnish (NFE) AF: 0.0274 AC: 30412 AN: 1111296

Other (OTH) AF: 0.0285 AC: 1720 AN: 60280

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

African (AFR) AF: 0.0352 AC: 1462 AN: 41556

American (AMR) AF: 0.0224 AC: 342 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0308 AC: 149 AN: 4830

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10626

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1923 AN: 68012

Other (OTH) AF: 0.0318 AC: 67 AN: 2108

Alfa AF: 0.0281 Hom.: 199

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.8
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.18
Sift	Benign	0.080	T
Sift4G	Benign	0.25	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
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35168378; hg19: chr16-920870; COSMIC: COSV51896016; COSMIC: COSV51896016;