chr3-45958418-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_024513.4(FYCO1):c.3789A>G(p.Thr1263Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,612,242 control chromosomes in the GnomAD database, including 886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 76 hom., cov: 33)

Exomes 𝑓: 0.032 ( 810 hom. )

Consequence

FYCO1
NM_024513.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.140

Publications

4 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.02).

BP6

Variant 3-45958418-T-C is Benign according to our data. Variant chr3-45958418-T-C is described in ClinVar as Benign. ClinVar VariationId is 345501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0258 (3935/152350) while in subpopulation NFE AF = 0.0386 (2623/68028). AF 95% confidence interval is 0.0373. There are 76 homozygotes in GnomAd4. There are 1890 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 76 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4 link	c.3789A>G	p.Thr1263Thr	synonymous_variant	Exon 13 of 18	ENST00000296137.7	NP_078789.2	Q9BQS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FYCO1	ENST00000296137.7 link	c.3789A>G	p.Thr1263Thr	synonymous_variant	Exon 13 of 18	1	NM_024513.4	ENSP00000296137.2	Q9BQS8-1
FYCO1	ENST00000433878.5 link	c.153A>G	p.Thr51Thr	synonymous_variant	Exon 1 of 7	2		ENSP00000388136.1	H7BZ74
FYCO1	ENST00000438446.1 link	c.-199A>G		5_prime_UTR_variant	Exon 1 of 6	5		ENSP00000398517.1	C9J2W6

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3938

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00627

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0277

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00620

Gnomad FIN

AF:

0.0396

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0386

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0287

AC:

7143

AN:

249260

AF XY:

0.0289

show subpopulations

Gnomad AFR exome

AF:

0.00520

Gnomad AMR exome

AF:

0.0237

Gnomad ASJ exome

AF:

0.0309

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0403

Gnomad NFE exome

AF:

0.0417

Gnomad OTH exome

AF:

0.0351

GnomAD4 exome

AF:

0.0317

AC:

46206

AN:

1459892

Hom.:

810

Cov.:

AF XY:

0.0312

AC XY:

22693

AN XY:

726226

show subpopulations

African (AFR)

AF:

0.00464

AC:

155

AN:

33420

American (AMR)

AF:

0.0253

AC:

1129

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0320

AC:

837

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00721

AC:

621

AN:

86134

European-Finnish (FIN)

AF:

0.0421

AC:

2243

AN:

53314

Middle Eastern (MID)

AF:

0.0380

AC:

170

AN:

4476

European-Non Finnish (NFE)

AF:

0.0353

AC:

39293

AN:

1111826

Other (OTH)

AF:

0.0292

AC:

1757

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

2390

4780

7171

9561

11951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1374

2748

4122

5496

6870

<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:

0.0258

AC:

3935

AN:

152350

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1890

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00625

AC:

260

AN:

41592

American (AMR)

AF:

0.0277

AC:

424

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00579

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0396

AC:

421

AN:

10620

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0386

AC:

2623

AN:

68028

Other (OTH)

AF:

0.0317

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

198

397

595

794

992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0340

Hom.:

210

Bravo

AF:

0.0244

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0403

EpiControl

AF:

0.0377

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 18

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.9

(source)

DANN

Benign

0.37

PhyloP100

-0.14

PromoterAI

-0.021

Neutral

(source)

Mutation Taster

=300/0

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