16-854551-G-T

Variant names:

• chr16-854551-G-T
• rs4984948
• NM_022773.4:c.1685C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022773.4(LMF1):​c.1685C>A​(p.Pro562His) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P562R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LMF1 NM_022773.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.50
• Publications: 0 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

ENSG00000287855 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1685C>A	p.Pro562His	missense	Exon 11 of 11	NP_073610.2	Q96S06-1
	LMF1	NM_001352019.2		c.1358C>A	p.Pro453His	missense	Exon 11 of 11	NP_001338948.1
	LMF1	NM_001352018.2		c.1286C>A	p.Pro429His	missense	Exon 12 of 12	NP_001338947.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LMF1	ENST00000262301.16	TSL:5 MANE Select	c.1685C>A	p.Pro562His	missense	Exon 11 of 11	ENSP00000262301.12	Q96S06-1
	LMF1	ENST00000565276.5	TSL:1	n.*680C>A		non_coding_transcript_exon	Exon 3 of 3	ENSP00000455930.1	H3BQT4
	LMF1	ENST00000565276.5	TSL:1	n.*680C>A		3_prime_UTR	Exon 3 of 3	ENSP00000455930.1	H3BQT4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724164

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111104

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.5
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.21
Sift	Benign	0.033	D
Sift4G	Benign	0.077	T
Polyphen		0.98	D
Vest4		0.45
MutPred		0.21		Loss of glycosylation at P562 (P = 0.0566)
MVP		0.43
MPC		0.14
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.38
gMVP		0.61

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: rs4984948; hg19: chr16-904551;