3-45968372-C-G

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.962G>C(p.Gly321Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,613,190 control chromosomes in the GnomAD database, including 242,056 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. G321C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.48 ( 19302 hom., cov: 32)

Exomes 𝑓: 0.55 ( 222754 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.49

Publications

42 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=2.394217E-6).

BP6

Variant 3-45968372-C-G is Benign according to our data. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in CliVar as Benign. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4 link	c.962G>C	p.Gly321Ala	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.962G>C	p.Gly321Ala	missense_variant	Exon 8 of 18	1	NM_024513.4	ENSP00000296137.2		Q9BQS8-1

Frequencies

GnomAD3 genomes

AF:

0.477

AC:

72518

AN:

151916

Hom.:

19287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.596

Gnomad AMR

AF:

0.600

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.680

Gnomad SAS

AF:

0.709

Gnomad FIN

AF:

0.621

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.533

Gnomad OTH

AF:

0.490

GnomAD2 exomes

AF:

0.577

AC:

144817

AN:

250930

AF XY:

0.583

show subpopulations

Gnomad AFR exome

AF:

0.236

Gnomad AMR exome

AF:

0.677

Gnomad ASJ exome

AF:

0.593

Gnomad EAS exome

AF:

0.676

Gnomad FIN exome

AF:

0.622

Gnomad NFE exome

AF:

0.538

Gnomad OTH exome

AF:

0.563

GnomAD4 exome

AF:

0.547

AC:

799313

AN:

1461156

Hom.:

222754

Cov.:

AF XY:

0.552

AC XY:

401240

AN XY:

726878

show subpopulations

African (AFR)

AF:

0.228

AC:

7626

AN:

33480

American (AMR)

AF:

0.668

AC:

29880

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.587

AC:

15343

AN:

26136

East Asian (EAS)

AF:

0.643

AC:

25520

AN:

39696

South Asian (SAS)

AF:

0.695

AC:

59926

AN:

86256

European-Finnish (FIN)

AF:

0.607

AC:

32080

AN:

52848

Middle Eastern (MID)

AF:

0.555

AC:

3204

AN:

5768

European-Non Finnish (NFE)

AF:

0.533

AC:

592178

AN:

1111864

Other (OTH)

AF:

0.556

AC:

33556

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

24048

48095

72143

96190

120238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16894

33788

50682

67576

84470

<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:

0.477

AC:

72557

AN:

152034

Hom.:

19302

Cov.:

AF XY:

0.489

AC XY:

36299

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.239

AC:

9900

AN:

41474

American (AMR)

AF:

0.600

AC:

9173

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

2030

AN:

3464

East Asian (EAS)

AF:

0.680

AC:

3504

AN:

5152

South Asian (SAS)

AF:

0.709

AC:

3417

AN:

4818

European-Finnish (FIN)

AF:

0.621

AC:

6557

AN:

10562

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.533

AC:

36241

AN:

67960

Other (OTH)

AF:

0.497

AC:

1048

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1748

3496

5243

6991

8739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.524

Hom.:

13650

Bravo

AF:

0.459

TwinsUK

AF:

0.536

AC:

1987

ALSPAC

AF:

0.542

AC:

2089

ESP6500AA

AF:

0.246

AC:

1086

ESP6500EA

AF:

0.544

AC:

4678

ExAC

AF:

0.567

AC:

68779

Asia WGS

AF:

0.693

AC:

2410

AN:

3478

EpiCase

AF:

0.539

EpiControl

AF:

0.543

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. -

Jan 31, 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

- -

Apr 02, 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

0.060

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.074

DEOGEN2

Benign

0.0022

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.16

T;T

MetaRNN

Benign

0.0000024

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

N;N

PhyloP100

2.5

PrimateAI

Benign

0.34

PROVEAN

Benign

1.7

N;N

REVEL

Benign

0.073

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.0080

MPC

0.17

ClinPred

0.00091

GERP RS

3.8

Varity_R

0.022

gMVP

0.046

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

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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