1-171205578-G-A
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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):c.1127G>A(p.Gly376Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,461,078 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 (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
FMO2
NM_001460.5 missense
NM_001460.5 missense
Scores
10
5
2
Clinical Significance
Conservation
PhyloP100: 8.14
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, 0.989
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FMO2 | NM_001460.5 | c.1127G>A | p.Gly376Asp | missense_variant | 7/9 | ENST00000209929.10 | |
LOC124900413 | XR_007066731.1 | n.366-8640C>T | intron_variant, non_coding_transcript_variant | ||||
LOC105371611 | XR_922278.4 | n.515-37390C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FMO2 | ENST00000209929.10 | c.1127G>A | p.Gly376Asp | missense_variant | 7/9 | 1 | NM_001460.5 | P1 | |
ENST00000445290.1 | n.139-6063C>T | intron_variant, non_coding_transcript_variant | 2 | ||||||
ENST00000669750.1 | n.449-37390C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247762Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134074
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461078Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 726804
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GnomAD4 genome Cov.: 32
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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 18, 2022 | The c.1127G>A (p.G376D) alteration is located in exon 7 (coding exon 6) of the FMO2 gene. This alteration results from a G to A substitution at nucleotide position 1127, causing the glycine (G) at amino acid position 376 to be replaced by an aspartic acid (D). 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
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MutPred
Gain of sheet (P = 0.1945);
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