chr3-45966333-T-C

Position:

chr3-45966333-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024513.4(FYCO1):c.3001A>G(p.Asn1001Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,892 control chromosomes in the GnomAD database, including 14,017 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. N1001E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.093 ( 1007 hom., cov: 33)

Exomes 𝑓: 0.12 ( 13010 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.912

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027463734).

BP6

Variant 3-45966333-T-C is Benign according to our data. Variant chr3-45966333-T-C is described in ClinVar as [Benign]. Clinvar id is 261728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45966333-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4 linkuse as main transcript	c.3001A>G	p.Asn1001Asp	missense_variant	8/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7 linkuse as main transcript	c.3001A>G	p.Asn1001Asp	missense_variant	8/18	1	NM_024513.4	P1	Q9BQS8-1

Frequencies

GnomAD3 genomes

AF:

0.0934

AC:

14209

AN:

152086

Hom.:

1008

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.0693

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.00367

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.0981

GnomAD3 exomes

AF:

0.127

AC:

31697

AN:

249768

Hom.:

3087

AF XY:

0.142

AC XY:

19123

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.0287

Gnomad AMR exome

AF:

0.0647

Gnomad ASJ exome

AF:

0.200

Gnomad EAS exome

AF:

0.00266

Gnomad SAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.117

AC:

170442

AN:

1461688

Hom.:

13010

Cov.:

AF XY:

0.125

AC XY:

90798

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0294

Gnomad4 AMR exome

AF:

0.0669

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.00204

Gnomad4 SAS exome

AF:

0.335

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.105

Gnomad4 OTH exome

AF:

0.121

GnomAD4 genome

AF:

0.0933

AC:

14205

AN:

152204

Hom.:

1007

Cov.:

AF XY:

0.0989

AC XY:

7360

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0305

Gnomad4 AMR

AF:

0.0691

Gnomad4 ASJ

AF:

0.196

Gnomad4 EAS

AF:

0.00368

Gnomad4 SAS

AF:

0.342

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.111

Gnomad4 OTH

AF:

0.0990

Alfa

AF:

0.0921

Hom.:

446

Bravo

AF:

0.0775

TwinsUK

AF:

0.100

AC:

371

ALSPAC

AF:

0.0996

AC:

384

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.129

AC:

15646

Asia WGS

AF:

0.172

AC:

599

AN:

3478

EpiCase

AF:

0.121

EpiControl

AF:

0.115

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 18

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.42

DEOGEN2

Benign

0.0012

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.13

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.1

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

0.49

N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.012

MPC

0.18

ClinPred

0.00036

GERP RS

2.3

Varity_R

0.046

gMVP

0.060

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over