1-171332743-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002022.3(FMO4):c.662T>A(p.Leu221His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,611,478 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (22 hom.)
• Consequence: FMO4 NM_002022.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.155

Genes affected

FMO4 (HGNC:3772): (flavin containing dimethylaniline monoxygenase 4) Metabolic N-oxidation of diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man. This results in a small subpopulation with reduced TMA N-oxidation capacity and causes fish odor syndrome (Trimethylaminuria). Three forms of the enzyme are encoded by genes clustered in the 1q23-q25 region. Flavin-containing monooxygenases are NADPH-dependent flavoenzymes that catalyzes the oxidation of soft nucleophilic heteroatom centers in drugs, pesticides, and xenobiotics. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011537373).
• BP6: Variant 1-171332743-T-A is Benign according to our data. Variant chr1-171332743-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 718489.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO4	NM_002022.3	c.662T>A	p.Leu221His	missense_variant	7/10	ENST00000367749.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO4	ENST00000367749.4	c.662T>A	p.Leu221His	missense_variant	7/10	1	NM_002022.3	P1
FMO4	ENST00000462992.1	n.428T>A		non_coding_transcript_exon_variant	4/4	3
FMO4	ENST00000475780.5	n.652-4613T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 504 AN: 152202 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00516

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00307 AC: 771 AN: 251114 Hom.: 3 AF XY: 0.00298 AC XY: 404 AN XY: 135700

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00439

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00461 AC: 6725 AN: 1459158 Hom.: 22 Cov.: 29 AF XY: 0.00432 AC XY: 3136 AN XY: 726118

Gnomad4 AFR exome AF: 0.000659

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.00401

Gnomad4 NFE exome AF: 0.00534

Gnomad4 OTH exome AF: 0.00493

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152320 Hom.: 3 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74484

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00555

Gnomad4 NFE AF: 0.00516

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00418 Hom.: 1

Bravo AF: 0.00297

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00504

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.19
Sift	Benign	0.043	D
Sift4G	Benign	0.082	T
Polyphen		0.97	D
Vest4		0.29
MVP		0.50
MPC		0.30
ClinPred		0.082	T
GERP RS		-5.2
Varity_R		0.29
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs61747501; hg19: chr1-171301882;