3-45968372-C-G

Position:

chr3-45968372-C-G

Variant summary

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

The NM_024513.4(FYCO1):c.962G>C(p.Gly321Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,613,190 control chromosomes in the GnomAD database, including 242,056 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 0.48 ( 19302 hom., cov: 32)

Exomes 𝑓: 0.55 ( 222754 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.49

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=2.394217E-6).

BP6

Variant 3-45968372-C-G is Benign according to our data. Variant chr3-45968372-C-G is described in ClinVar as [Benign]. Clinvar id is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45968372-C-G is described in Lovd as [Benign]. Variant chr3-45968372-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.689 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.962G>C	p.Gly321Ala	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.962G>C	p.Gly321Ala	missense_variant	8/18	1	NM_024513.4	P1	Q9BQS8-1

Frequencies

GnomAD3 genomes

AF:

0.477

AC:

72518

AN:

151916

Hom.:

19287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.596

Gnomad AMR

AF:

0.600

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.680

Gnomad SAS

AF:

0.709

Gnomad FIN

AF:

0.621

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.533

Gnomad OTH

AF:

0.490

GnomAD3 exomes

AF:

0.577

AC:

144817

AN:

250930

Hom.:

43499

AF XY:

0.583

AC XY:

79086

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.236

Gnomad AMR exome

AF:

0.677

Gnomad ASJ exome

AF:

0.593

Gnomad EAS exome

AF:

0.676

Gnomad SAS exome

AF:

0.699

Gnomad FIN exome

AF:

0.622

Gnomad NFE exome

AF:

0.538

Gnomad OTH exome

AF:

0.563

GnomAD4 exome

AF:

0.547

AC:

799313

AN:

1461156

Hom.:

222754

Cov.:

AF XY:

0.552

AC XY:

401240

AN XY:

726878

show subpopulations

Gnomad4 AFR exome

AF:

0.228

Gnomad4 AMR exome

AF:

0.668

Gnomad4 ASJ exome

AF:

0.587

Gnomad4 EAS exome

AF:

0.643

Gnomad4 SAS exome

AF:

0.695

Gnomad4 FIN exome

AF:

0.607

Gnomad4 NFE exome

AF:

0.533

Gnomad4 OTH exome

AF:

0.556

GnomAD4 genome

AF:

0.477

AC:

72557

AN:

152034

Hom.:

19302

Cov.:

AF XY:

0.489

AC XY:

36299

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.239

Gnomad4 AMR

AF:

0.600

Gnomad4 ASJ

AF:

0.586

Gnomad4 EAS

AF:

0.680

Gnomad4 SAS

AF:

0.709

Gnomad4 FIN

AF:

0.621

Gnomad4 NFE

AF:

0.533

Gnomad4 OTH

AF:

0.497

Alfa

AF:

0.524

Hom.:

13650

Bravo

AF:

0.459

TwinsUK

AF:

0.536

AC:

1987

ALSPAC

AF:

0.542

AC:

2089

ESP6500AA

AF:

0.246

AC:

1086

ESP6500EA

AF:

0.544

AC:

4678

ExAC

AF:

0.567

AC:

68779

Asia WGS

AF:

0.693

AC:

2410

AN:

3478

EpiCase

AF:

0.539

EpiControl

AF:

0.543

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	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	Invitae	Jan 27, 2024	- -

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

Apr 02, 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

0.060

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.074

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.16

T;T

MetaRNN

Benign

0.0000024

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

1.7

N;N

REVEL

Benign

0.073

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.0080

MPC

0.17

ClinPred

0.00091

GERP RS

3.8

Varity_R

0.022

gMVP

0.046

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