rs9875356

chr3-45968489-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024513.4(FYCO1):c.845G>A(p.Arg282His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,613,998 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (73 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (83 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.238

Genes affected

FYCO1 (HGNC:14673): (FYVE and coiled-coil domain autophagy adaptor 1) The gene encodes a Rab7 adapter protein that is implicated in the microtubule transport of autophagosomes. The encoded protein contains a RUN domain, a FYVE-type zinc finger domain, and Golgi dynamics (GOLD) domain. The encoded protein plays a role in microtubule plus end-directed transport of autophagic vesicles through interactions with the small GTPase Rab7, phosphatidylinositol-3-phosphate (PI3P), the autophagosome marker LC3, and the kinesin KIF5. Mutations in this gene are associated with inclusion body myositis (IBM) and autosomal recessive congenital cataracts (CATC2). [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019890368).
• BP6: Variant 3-45968489-C-T is Benign according to our data. Variant chr3-45968489-C-T is described in ClinVar as [Benign]. Clinvar id is 345534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.845G>A	p.Arg282His	missense_variant	8/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.845G>A	p.Arg282His	missense_variant	8/18	1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2602 AN: 152214 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00948

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00523 AC: 1315 AN: 251288 Hom.: 29 AF XY: 0.00385 AC XY: 523 AN XY: 135854

Gnomad AFR exome AF: 0.0614

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00245 AC: 3579 AN: 1461666 Hom.: 83 Cov.: 84 AF XY: 0.00221 AC XY: 1607 AN XY: 727160

Gnomad4 AFR exome AF: 0.0634

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000669

Gnomad4 OTH exome AF: 0.00563

GnomAD4 genome AF: 0.0172 AC: 2616 AN: 152332 Hom.: 73 Cov.: 33 AF XY: 0.0164 AC XY: 1225 AN XY: 74496

Gnomad4 AFR AF: 0.0574

Gnomad4 AMR AF: 0.00947

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00500 Hom.: 23

Bravo AF: 0.0202

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0590 AC: 260

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00619 AC: 751

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	10
Dann	Benign	0.22
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.0060
Sift	Benign	0.58	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.010	.;B
Vest4		0.046
MVP		0.31
MPC		0.20
ClinPred		0.0011	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.070

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: rs9875356; hg19: chr3-46009981;