Genetic Variant LMF1:c.514+2452G>A (chr16-931792-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001352017.2(LMF1):c.-288G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,286,224 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 13 hom. )

Consequence

LMF1
NM_001352017.2 splice_region

Scores

Splicing: ADA: 0.00002453

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.76

Publications

0 publications found

Variant links:

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 links:

LMF1-AS1 (HGNC:50469): (LMF1 antisense RNA 1)

LMF1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 16-931792-C-T is Benign according to our data. Variant chr16-931792-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2584630.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00336 (512/152312) while in subpopulation NFE AF = 0.00535 (364/68034). AF 95% confidence interval is 0.0049. There are 2 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352017.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LMF1	NM_022773.4	MANE Select	c.514+2452G>A	intron	N/A	NP_073610.2	Q96S06-1
LMF1	NM_001352017.2		c.-288G>A	splice_region	Exon 4 of 12	NP_001338946.1	H3BVI4
LMF1	NM_001352017.2		c.-288G>A	5_prime_UTR	Exon 4 of 12	NP_001338946.1	H3BVI4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LMF1	ENST00000262301.16	TSL:5 MANE Select	c.514+2452G>A	intron	N/A	ENSP00000262301.12	Q96S06-1
LMF1	ENST00000963976.1		c.514+2452G>A	intron	N/A	ENSP00000634035.1
LMF1	ENST00000568897.5	TSL:5	c.-137-20713G>A	intron	N/A	ENSP00000458135.1	H3BVI4

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

513

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00535

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00391

AC:

501

AN:

127986

AF XY:

0.00381

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.00316

Gnomad ASJ exome

AF:

0.00729

Gnomad EAS exome

AF:

0.0000959

Gnomad FIN exome

AF:

0.00353

Gnomad NFE exome

AF:

0.00592

Gnomad OTH exome

AF:

0.00451

GnomAD4 exome

AF:

0.00409

AC:

4635

AN:

1133912

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

2283

AN XY:

555976

show subpopulations

African (AFR)

AF:

0.000493

AC:

AN:

24322

American (AMR)

AF:

0.00294

AC:

AN:

28244

Ashkenazi Jewish (ASJ)

AF:

0.00672

AC:

107

AN:

15926

East Asian (EAS)

AF:

0.0000782

AC:

AN:

12790

South Asian (SAS)

AF:

0.00254

AC:

193

AN:

76084

European-Finnish (FIN)

AF:

0.00308

AC:

AN:

12642

Middle Eastern (MID)

AF:

0.00759

AC:

AN:

2768

European-Non Finnish (NFE)

AF:

0.00437

AC:

4022

AN:

919824

Other (OTH)

AF:

0.00380

AC:

157

AN:

41312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

227

454

682

909

1136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00336

AC:

512

AN:

152312

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

226

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41566

American (AMR)

AF:

0.00222

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00311

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00535

AC:

364

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00468

Hom.:

Bravo

AF:

0.00323

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lipase deficiency, combined (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

(source)

DANN

Benign

0.59

PhyloP100

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000025

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.50

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.50

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over