3-45968585-C-T

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.749G>A(p.Arg250Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,613,920 control chromosomes in the GnomAD database, including 516,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R250W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.85 ( 55375 hom., cov: 33)

Exomes 𝑓: 0.79 ( 461193 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.16

Publications

44 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=8.2639644E-7).

BP6

Variant 3-45968585-C-T is Benign according to our data. Variant chr3-45968585-C-T is described in ClinVar as Benign. ClinVar VariationId is 261736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4 link	c.749G>A	p.Arg250Gln	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.749G>A	p.Arg250Gln	missense_variant	Exon 8 of 18	1	NM_024513.4	ENSP00000296137.2		Q9BQS8-1

Frequencies

GnomAD3 genomes

AF:

0.848

AC:

129014

AN:

152118

Hom.:

55309

Cov.:

show subpopulations

Gnomad AFR

AF:

0.951

Gnomad AMI

AF:

0.658

Gnomad AMR

AF:

0.895

Gnomad ASJ

AF:

0.841

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.913

Gnomad FIN

AF:

0.808

Gnomad MID

AF:

0.880

Gnomad NFE

AF:

0.767

Gnomad OTH

AF:

0.857

GnomAD2 exomes

AF:

0.847

AC:

212848

AN:

251310

AF XY:

0.843

show subpopulations

Gnomad AFR exome

AF:

0.956

Gnomad AMR exome

AF:

0.925

Gnomad ASJ exome

AF:

0.846

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.811

Gnomad NFE exome

AF:

0.776

Gnomad OTH exome

AF:

0.836

GnomAD4 exome

AF:

0.792

AC:

1156949

AN:

1461684

Hom.:

461193

Cov.:

AF XY:

0.795

AC XY:

577772

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.962

AC:

32195

AN:

33480

American (AMR)

AF:

0.920

AC:

41148

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.846

AC:

22109

AN:

26136

East Asian (EAS)

AF:

0.999

AC:

39679

AN:

39700

South Asian (SAS)

AF:

0.901

AC:

77712

AN:

86258

European-Finnish (FIN)

AF:

0.806

AC:

42926

AN:

53230

Middle Eastern (MID)

AF:

0.904

AC:

5216

AN:

5768

European-Non Finnish (NFE)

AF:

0.761

AC:

846185

AN:

1111996

Other (OTH)

AF:

0.824

AC:

49779

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16081

32161

48242

64322

80403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20452

40904

61356

81808

102260

<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:

0.848

AC:

129140

AN:

152236

Hom.:

55375

Cov.:

AF XY:

0.853

AC XY:

63447

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.951

AC:

39523

AN:

41540

American (AMR)

AF:

0.895

AC:

13692

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.841

AC:

2920

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5170

AN:

5174

South Asian (SAS)

AF:

0.913

AC:

4405

AN:

4824

European-Finnish (FIN)

AF:

0.808

AC:

8557

AN:

10588

Middle Eastern (MID)

AF:

0.884

AC:

260

AN:

294

European-Non Finnish (NFE)

AF:

0.767

AC:

52197

AN:

68018

Other (OTH)

AF:

0.859

AC:

1816

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

989

1978

2968

3957

4946

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<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:

0.805

Hom.:

123001

Bravo

AF:

0.861

TwinsUK

AF:

0.766

AC:

2841

ALSPAC

AF:

0.761

AC:

2931

ESP6500AA

AF:

0.944

AC:

4160

ESP6500EA

AF:

0.775

AC:

6662

ExAC

AF:

0.847

AC:

102808

Asia WGS

AF:

0.963

AC:

3346

AN:

3478

EpiCase

AF:

0.783

EpiControl

AF:

0.783

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 18

Benign:3

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

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

- -

Mar 24, 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

0.052

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0035

.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.20

T;T

MetaRNN

Benign

8.3e-7

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.7

N;N

PhyloP100

2.2

PrimateAI

Benign

0.38

PROVEAN

Benign

1.6

N;N

REVEL

Benign

0.083

Sift

Benign

0.37

T;T

Sift4G

Benign

0.68

T;T

Polyphen

0.0

.;B

Vest4

0.030

MPC

0.18

ClinPred

0.019

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.027

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