rs3796375

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.2036C>T(p.Ala679Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,613,460 control chromosomes in the GnomAD database, including 149,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A679A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.36 ( 11902 hom., cov: 32)

Exomes 𝑓: 0.43 ( 137501 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.12

Publications

47 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=2.427137E-5).

BP6

Variant 3-45967298-G-A is Benign according to our data. Variant chr3-45967298-G-A is described in ClinVar as Benign. ClinVar VariationId is 261722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024513.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FYCO1	NM_024513.4	MANE Select	c.2036C>T	p.Ala679Val	missense	Exon 8 of 18	NP_078789.2	Q9BQS8-1
FYCO1	NM_001386421.1		c.2036C>T	p.Ala679Val	missense	Exon 9 of 19	NP_001373350.1	Q9BQS8-1
FYCO1	NM_001386422.1		c.2036C>T	p.Ala679Val	missense	Exon 8 of 18	NP_001373351.1	Q9BQS8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.2036C>T	p.Ala679Val	missense	Exon 8 of 18	ENSP00000296137.2	Q9BQS8-1
FYCO1	ENST00000874259.1		c.2036C>T	p.Ala679Val	missense	Exon 9 of 19	ENSP00000544318.1
FYCO1	ENST00000965269.1		c.2036C>T	p.Ala679Val	missense	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes

AF:

0.362

AC:

55046

AN:

151882

Hom.:

11889

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.368

Gnomad AMR

AF:

0.518

Gnomad ASJ

AF:

0.388

Gnomad EAS

AF:

0.673

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.476

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.372

GnomAD2 exomes

AF:

0.443

AC:

111217

AN:

250966

AF XY:

0.436

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.606

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.669

Gnomad FIN exome

AF:

0.475

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.429

GnomAD4 exome

AF:

0.427

AC:

624484

AN:

1461460

Hom.:

137501

Cov.:

AF XY:

0.424

AC XY:

308494

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.121

AC:

4057

AN:

33474

American (AMR)

AF:

0.594

AC:

26580

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

10181

AN:

26132

East Asian (EAS)

AF:

0.639

AC:

25349

AN:

39694

South Asian (SAS)

AF:

0.360

AC:

31020

AN:

86256

European-Finnish (FIN)

AF:

0.463

AC:

24590

AN:

53134

Middle Eastern (MID)

AF:

0.348

AC:

2005

AN:

5762

European-Non Finnish (NFE)

AF:

0.427

AC:

474877

AN:

1111904

Other (OTH)

AF:

0.428

AC:

25825

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

22011

44021

66032

88042

110053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14538

29076

43614

58152

72690

<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:

0.362

AC:

55074

AN:

152000

Hom.:

11902

Cov.:

AF XY:

0.369

AC XY:

27420

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.137

AC:

5680

AN:

41498

American (AMR)

AF:

0.518

AC:

7915

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

1348

AN:

3470

East Asian (EAS)

AF:

0.673

AC:

3465

AN:

5148

South Asian (SAS)

AF:

0.368

AC:

1770

AN:

4816

European-Finnish (FIN)

AF:

0.476

AC:

5032

AN:

10566

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.422

AC:

28645

AN:

67924

Other (OTH)

AF:

0.378

AC:

797

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1618

3235

4853

6470

8088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.414

Hom.:

61730

Bravo

AF:

0.356

TwinsUK

AF:

0.432

AC:

1603

ALSPAC

AF:

0.439

AC:

1690

ESP6500AA

AF:

0.142

AC:

626

ESP6500EA

AF:

0.431

AC:

3706

ExAC

AF:

0.429

AC:

52128

Asia WGS

AF:

0.510

AC:

1772

AN:

3478

EpiCase

AF:

0.417

EpiControl

AF:

0.426

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 18 (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.73

MetaRNN

Benign

0.000024

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

PhyloP100

3.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

REVEL

Benign

0.072

Sift

Benign

0.22

Sift4G

Benign

0.15

Polyphen

0.99

Vest4

0.038

MPC

0.34

ClinPred

0.025

GERP RS

3.5

Varity_R

0.075

gMVP

0.080

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over