chr3-45967995-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024513.4(FYCO1):c.1339C>T(p.Arg447Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,916 control chromosomes in the GnomAD database, including 13,793 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R447H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.092 ( 1004 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12789 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.816

Publications

36 publications found

Variant links:

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]

FYCO1 Gene-Disease associations (from GenCC):

cataract 18
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
total early-onset cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FYCO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002291739).

BP6

Variant 3-45967995-G-A is Benign according to our data. Variant chr3-45967995-G-A is described in ClinVar as Benign. ClinVar VariationId is 261720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4 link	c.1339C>T	p.Arg447Cys	missense_variant	Exon 8 of 18	ENST00000296137.7	NP_078789.2	Q9BQS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7 link	c.1339C>T	p.Arg447Cys	missense_variant	Exon 8 of 18	1	NM_024513.4	ENSP00000296137.2		Q9BQS8-1

Frequencies

GnomAD3 genomes

AF:

0.0922

AC:

14006

AN:

151952

Hom.:

1005

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0300

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.0665

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00367

Gnomad SAS

AF:

0.340

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.0943

GnomAD2 exomes

AF:

0.125

AC:

31541

AN:

251438

AF XY:

0.140

show subpopulations

Gnomad AFR exome

AF:

0.0281

Gnomad AMR exome

AF:

0.0613

Gnomad ASJ exome

AF:

0.187

Gnomad EAS exome

AF:

0.00272

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.115

AC:

168692

AN:

1461846

Hom.:

12789

Cov.:

AF XY:

0.124

AC XY:

89921

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0277

AC:

927

AN:

33480

American (AMR)

AF:

0.0633

AC:

2832

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.180

AC:

4710

AN:

26136

East Asian (EAS)

AF:

0.00207

AC:

AN:

39698

South Asian (SAS)

AF:

0.335

AC:

28876

AN:

86258

European-Finnish (FIN)

AF:

0.144

AC:

7697

AN:

53402

Middle Eastern (MID)

AF:

0.189

AC:

1091

AN:

5768

European-Non Finnish (NFE)

AF:

0.104

AC:

115348

AN:

1111984

Other (OTH)

AF:

0.118

AC:

7129

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

10553

21106

31660

42213

52766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4146

8292

12438

16584

20730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0921

AC:

13999

AN:

152070

Hom.:

1004

Cov.:

AF XY:

0.0979

AC XY:

7280

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0298

AC:

1238

AN:

41490

American (AMR)

AF:

0.0664

AC:

1015

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

629

AN:

3468

East Asian (EAS)

AF:

0.00368

AC:

AN:

5168

South Asian (SAS)

AF:

0.340

AC:

1636

AN:

4806

European-Finnish (FIN)

AF:

0.145

AC:

1533

AN:

10562

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7470

AN:

67968

Other (OTH)

AF:

0.0953

AC:

201

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

577

1154

1732

2309

2886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.101

Hom.:

2210

Bravo

AF:

0.0756

TwinsUK

AF:

0.102

AC:

378

ALSPAC

AF:

0.101

AC:

390

ESP6500AA

AF:

0.0309

AC:

136

ESP6500EA

AF:

0.110

AC:

948

ExAC

AF:

0.128

AC:

15483

Asia WGS

AF:

0.169

AC:

588

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.113

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 18

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.6

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.025

.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L

PhyloP100

-0.82

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.059

Sift

Benign

0.048

D;D

Sift4G

Uncertain

0.037

D;D

Polyphen

0.95

.;P

Vest4

0.051

MPC

0.22

ClinPred

0.0036

GERP RS

-5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.079

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over