1-171199382-G-A

Position:

• chr1-171199382-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001460.5(FMO2):​c.521G>A​(p.Arg174His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00661 in 1,610,194 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (41 hom.)
• Consequence: FMO2 NM_001460.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.56

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013393253).
• BP6: Variant 1-171199382-G-A is Benign according to our data. Variant chr1-171199382-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 709846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FMO2	NM_001460.5	c.521G>A	p.Arg174His	missense_variant	5/9	ENST00000209929.10
LOC124900413	XR_007066731.1	n.366-2444C>T		intron_variant, non_coding_transcript_variant
LOC105371611	XR_922278.4	n.515-31194C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FMO2	ENST00000209929.10	c.521G>A	p.Arg174His	missense_variant	5/9	1	NM_001460.5	P1
	ENST00000445290.1	n.272C>T		non_coding_transcript_exon_variant	2/2	2
	ENST00000669750.1	n.449-31194C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 756 AN: 152092 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00636

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00581

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00455 AC: 1126 AN: 247490 Hom.: 6 AF XY: 0.00478 AC XY: 639 AN XY: 133794

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.00361

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00418

Gnomad FIN exome AF: 0.00330

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00516

GnomAD4 exome AF: 0.00678 AC: 9892 AN: 1457984 Hom.: 41 Cov.: 30 AF XY: 0.00672 AC XY: 4872 AN XY: 725226

Gnomad4 AFR exome AF: 0.000813

Gnomad4 AMR exome AF: 0.00319

Gnomad4 ASJ exome AF: 0.00461

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00402

Gnomad4 FIN exome AF: 0.00322

Gnomad4 NFE exome AF: 0.00779

Gnomad4 OTH exome AF: 0.00672

GnomAD4 genome AF: 0.00496 AC: 755 AN: 152210 Hom.: 8 Cov.: 32 AF XY: 0.00469 AC XY: 349 AN XY: 74418

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00635

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00582

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00716

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00622 Hom.: 4

Bravo AF: 0.00505

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00434 AC: 527

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.35
Sift	Benign	0.14	T
Sift4G	Benign	0.28	T
Vest4		0.27
MVP		0.70
ClinPred		0.028	T
GERP RS		5.3
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs148292940; hg19: chr1-171168521; COSMIC: COSV52950204; COSMIC: COSV52950204;