chr3-45923698-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024513.4(FYCO1):c.4319C>T(p.Thr1440Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00554 in 1,614,120 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0057 ( 34 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.03

Publications

5 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014971375).

BP6

Variant 3-45923698-G-A is Benign according to our data. Variant chr3-45923698-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 345495.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00432 (658/152330) while in subpopulation AMR AF = 0.00732 (112/15310). AF 95% confidence interval is 0.00622. There are 1 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4 link	c.4319C>T	p.Thr1440Ile	missense_variant	Exon 17 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FYCO1	ENST00000296137.7 link	c.4319C>T	p.Thr1440Ile	missense_variant	Exon 17 of 18	1	NM_024513.4	ENSP00000296137.2
FYCO1	ENST00000433878.5 link	c.683C>T	p.Thr228Ile	missense_variant	Exon 5 of 7	2		ENSP00000388136.1
FYCO1	ENST00000438446.1 link	c.332C>T	p.Thr111Ile	missense_variant	Exon 5 of 6	5		ENSP00000398517.1

Frequencies

GnomAD3 genomes

AF:

0.00433

AC:

659

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00659

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00355

AC:

892

AN:

251478

AF XY:

0.00350

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00361

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00245

Gnomad NFE exome

AF:

0.00549

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00567

AC:

8289

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

4014

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00134

AC:

AN:

33476

American (AMR)

AF:

0.00373

AC:

167

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00147

AC:

127

AN:

86256

European-Finnish (FIN)

AF:

0.00249

AC:

133

AN:

53418

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00672

AC:

7473

AN:

1111926

Other (OTH)

AF:

0.00540

AC:

326

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

418

836

1254

1672

2090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.00432

AC:

658

AN:

152330

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41574

American (AMR)

AF:

0.00732

AC:

112

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00270

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00657

AC:

447

AN:

68022

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

106

141

176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00450

Hom.:

Bravo

AF:

0.00443

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00344

AC:

418

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00539

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FYCO1: BP4, BS2

Dec 17, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Cataract 18

Benign:2

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Inborn genetic diseases

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4319C>T (p.T1440I) alteration is located in exon 17 (coding exon 16) of the FYCO1 gene. This alteration results from a C to T substitution at nucleotide position 4319, causing the threonine (T) at amino acid position 1440 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;.

PhyloP100

4.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.22

T;T;T

Vest4

0.34

ClinPred

0.012

GERP RS

3.2

Varity_R

0.020

gMVP

0.26

Mutation Taster

=96/4

polymorphism

(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