chr3-45967995-G-A

Position:

chr3-45967995-G-A

Variant summary

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

The NM_024513.4(FYCO1):c.1339C>T(p.Arg447Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,916 control chromosomes in the GnomAD database, including 13,793 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 1004 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12789 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.816

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:

FYCO1 (HGNC:):

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=0.002291739).

BP6

Variant 3-45967995-G-A is Benign according to our data. Variant chr3-45967995-G-A is described in ClinVar as [Benign]. Clinvar id is 261720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45967995-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FYCO1	NM_024513.4 linkuse as main transcript	c.1339C>T	p.Arg447Cys	missense_variant	8/18	ENST00000296137.7	NP_078789.2	Q9BQS8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7 linkuse as main transcript	c.1339C>T	p.Arg447Cys	missense_variant	8/18	1	NM_024513.4	ENSP00000296137.2		Q9BQS8-1

Frequencies

GnomAD3 genomes

AF:

0.0922

AC:

14006

AN:

151952

Hom.:

1005

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0300

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.0665

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00367

Gnomad SAS

AF:

0.340

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.0943

GnomAD3 exomes

AF:

0.125

AC:

31541

AN:

251438

Hom.:

3091

AF XY:

0.140

AC XY:

19032

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0281

Gnomad AMR exome

AF:

0.0613

Gnomad ASJ exome

AF:

0.187

Gnomad EAS exome

AF:

0.00272

Gnomad SAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.124

GnomAD4 exome

AF:

0.115

AC:

168692

AN:

1461846

Hom.:

12789

Cov.:

AF XY:

0.124

AC XY:

89921

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0277

Gnomad4 AMR exome

AF:

0.0633

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.00207

Gnomad4 SAS exome

AF:

0.335

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.104

Gnomad4 OTH exome

AF:

0.118

GnomAD4 genome

AF:

0.0921

AC:

13999

AN:

152070

Hom.:

1004

Cov.:

AF XY:

0.0979

AC XY:

7280

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0298

Gnomad4 AMR

AF:

0.0664

Gnomad4 ASJ

AF:

0.181

Gnomad4 EAS

AF:

0.00368

Gnomad4 SAS

AF:

0.340

Gnomad4 FIN

AF:

0.145

Gnomad4 NFE

AF:

0.110

Gnomad4 OTH

AF:

0.0953

Alfa

AF:

0.103

Hom.:

1410

Bravo

AF:

0.0756

TwinsUK

AF:

0.102

AC:

378

ALSPAC

AF:

0.101

AC:

390

ESP6500AA

AF:

0.0309

AC:

136

ESP6500EA

AF:

0.110

AC:

948

ExAC

AF:

0.128

AC:

15483

Asia WGS

AF:

0.169

AC:

588

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.113

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 18

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.6

DANN

Benign

0.92

DEOGEN2

Benign

0.025

.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.059

Sift

Benign

0.048

D;D

Sift4G

Uncertain

0.037

D;D

Polyphen

0.95

.;P

Vest4

0.051

MPC

0.22

ClinPred

0.0036

GERP RS

-5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.057

gMVP

0.079

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