1-147201163-T-C

Position:

• chr1-147201163-T-C

Variant summary

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

The NM_001461.4(FMO5):​c.1172A>G​(p.Gln391Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,610,614 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (52 hom.)
• Consequence: FMO5 NM_001461.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.09

Genes affected

FMO5 (HGNC:3773): (flavin containing dimethylaniline monoxygenase 5) Metabolic N-oxidation of the diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man resulting in a small subpopulation with reduced TMA N-oxidation capacity resulting in fish odor syndrome Trimethylaminuria. Three forms of the enzyme, FMO1 found in fetal liver, FMO2 found in adult liver, and FMO3 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]

CHD1L (HGNC:1916): (chromodomain helicase DNA binding protein 1 like) This gene encodes a DNA helicase protein involved in DNA repair. The protein converts ATP to add poly(ADP-ribose) as it regulates chromatin relaxation following DNA damage. Overexpression of this gene has been linked to several types of cancers. [provided by RefSeq, Feb 2017]

ENSG00000237188 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007174343).
• BP6: Variant 1-147201163-T-C is Benign according to our data. Variant chr1-147201163-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 781779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FMO5	NM_001461.4	c.1172A>G	p.Gln391Arg	missense_variant	7/9	ENST00000254090.9	NP_001452.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FMO5	ENST00000254090.9	c.1172A>G	p.Gln391Arg	missense_variant	7/9	1	NM_001461.4	ENSP00000254090.4

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152188 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00464 AC: 1156 AN: 249154 Hom.: 14 AF XY: 0.00487 AC XY: 656 AN XY: 134734

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.0455

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00275

Gnomad FIN exome AF: 0.000419

Gnomad NFE exome AF: 0.00420

Gnomad OTH exome AF: 0.00742

GnomAD4 exome AF: 0.00475 AC: 6932 AN: 1458308 Hom.: 52 Cov.: 30 AF XY: 0.00481 AC XY: 3489 AN XY: 725528

Gnomad4 AFR exome AF: 0.000662

Gnomad4 AMR exome AF: 0.00285

Gnomad4 ASJ exome AF: 0.0452

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00312

Gnomad4 FIN exome AF: 0.000563

Gnomad4 NFE exome AF: 0.00441

Gnomad4 OTH exome AF: 0.00658

GnomAD4 genome AF: 0.00388 AC: 591 AN: 152306 Hom.: 3 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74470

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00450

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00586 Hom.: 13

Bravo AF: 0.00390

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00408 AC: 495

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00539

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FMO5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.0066	.;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.4	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	2.7	N;.;N
REVEL	Benign	0.088
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.096
MVP		0.081
MPC		0.030
ClinPred		0.0082	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.66

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: rs56134376; hg19: chr1-146672745; COSMIC: COSV105029172; COSMIC: COSV105029172;