Genetic Variant NM_024513.4:c.3419G>A (chr3-45962243-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024513.4(FYCO1):c.3419G>A(p.Arg1140Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,124 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0082 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 112 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.59

Publications

14 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=0.008017093).

BP6

Variant 3-45962243-C-T is Benign according to our data. Variant chr3-45962243-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00821 (1250/152310) while in subpopulation NFE AF = 0.0119 (810/68018). AF 95% confidence interval is 0.0112. There are 7 homozygotes in GnomAd4. There are 586 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

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
FYCO1	NM_024513.4	MANE Select	c.3419G>A	p.Arg1140Gln	missense	Exon 11 of 18	NP_078789.2
FYCO1	NM_001386421.1		c.3419G>A	p.Arg1140Gln	missense	Exon 12 of 19	NP_001373350.1
FYCO1	NM_001386422.1		c.3419G>A	p.Arg1140Gln	missense	Exon 11 of 18	NP_001373351.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.3419G>A	p.Arg1140Gln	missense	Exon 11 of 18	ENSP00000296137.2
FYCO1	ENST00000874259.1		c.3419G>A	p.Arg1140Gln	missense	Exon 12 of 19	ENSP00000544318.1
FYCO1	ENST00000965269.1		c.3419G>A	p.Arg1140Gln	missense	Exon 11 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes

AF:

0.00821

AC:

1250

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0112

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00786

Gnomad FIN

AF:

0.00886

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.0107

AC:

2699

AN:

251452

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.0234

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0108

AC:

15854

AN:

1461814

Hom.:

112

Cov.:

AF XY:

0.0106

AC XY:

7697

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33480

American (AMR)

AF:

0.0208

AC:

932

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00344

AC:

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.00814

AC:

702

AN:

86254

European-Finnish (FIN)

AF:

0.0113

AC:

603

AN:

53420

Middle Eastern (MID)

AF:

0.00676

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0116

AC:

12890

AN:

1111942

Other (OTH)

AF:

0.00889

AC:

537

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

840

1679

2519

3358

4198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

500

1000

1500

2000

2500

<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:

0.00821

AC:

1250

AN:

152310

Hom.:

Cov.:

AF XY:

0.00787

AC XY:

586

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00250

AC:

104

AN:

41568

American (AMR)

AF:

0.0112

AC:

172

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00787

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00886

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

810

AN:

68018

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

135

203

270

338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00982

Hom.:

Bravo

AF:

0.00861

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0116

AC:

100

ExAC

AF:

0.0104

AC:

1266

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00987

EpiControl

AF:

0.0106

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Cataract 18 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.046

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0080

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

7.6

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.3

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.66

MPC

0.72

ClinPred

0.044

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.76

Mutation Taster

=97/3

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

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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