chr1-171205599-A-G
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001460.5(FMO2):āc.1148A>Gā(p.Glu383Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,612,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000046 ( 0 hom., cov: 32)
Exomes š: 0.000028 ( 0 hom. )
Consequence
FMO2
NM_001460.5 missense
NM_001460.5 missense
Scores
11
3
3
Clinical Significance
Conservation
PhyloP100: 9.31
Genes affected
FMO2 (HGNC:3770): (flavin containing dimethylaniline monoxygenase 2) This gene encodes a flavin-containing monooxygenase family member. It is an NADPH-dependent enzyme that catalyzes the N-oxidation of some primary alkylamines through an N-hydroxylamine intermediate. However, some human populations contain an allele (FMO2*2A) with a premature stop codon, resulting in a protein that is C-terminally-truncated, has no catalytic activity, and is likely degraded rapidly. This gene is found in a cluster with other related family members on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FMO2 | NM_001460.5 | c.1148A>G | p.Glu383Gly | missense_variant | 7/9 | ENST00000209929.10 | |
LOC124900413 | XR_007066731.1 | n.366-8661T>C | intron_variant, non_coding_transcript_variant | ||||
LOC105371611 | XR_922278.4 | n.515-37411T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FMO2 | ENST00000209929.10 | c.1148A>G | p.Glu383Gly | missense_variant | 7/9 | 1 | NM_001460.5 | P1 | |
ENST00000445290.1 | n.139-6084T>C | intron_variant, non_coding_transcript_variant | 2 | ||||||
ENST00000669750.1 | n.449-37411T>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000122 AC: 3AN: 246770Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133542
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GnomAD4 exome AF: 0.0000281 AC: 41AN: 1460256Hom.: 0 Cov.: 32 AF XY: 0.0000207 AC XY: 15AN XY: 726336
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 16, 2024 | The c.1148A>G (p.E383G) alteration is located in exon 7 (coding exon 6) of the FMO2 gene. This alteration results from a A to G substitution at nucleotide position 1148, causing the glutamic acid (E) at amino acid position 383 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0479);
MVP
ClinPred
D
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at