rs3796375

Positions:

chr3-45967298-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.2036C>T(p.Ala679Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,613,460 control chromosomes in the GnomAD database, including 149,403 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A679A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.36 ( 11902 hom., cov: 32)

Exomes 𝑓: 0.43 ( 137501 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.12

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=2.427137E-5).

BP6

Variant 3-45967298-G-A is Benign according to our data. Variant chr3-45967298-G-A is described in ClinVar as [Benign]. Clinvar id is 261722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45967298-G-A is described in Lovd as [Benign]. Variant chr3-45967298-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.654 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.2036C>T	p.Ala679Val	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.2036C>T	p.Ala679Val	missense_variant	8/18	1	NM_024513.4	ENSP00000296137.2		Q9BQS8-1

Frequencies

GnomAD3 genomes

AF:

0.362

AC:

55046

AN:

151882

Hom.:

11889

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.368

Gnomad AMR

AF:

0.518

Gnomad ASJ

AF:

0.388

Gnomad EAS

AF:

0.673

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.476

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.372

GnomAD3 exomes

AF:

0.443

AC:

111217

AN:

250966

Hom.:

26777

AF XY:

0.436

AC XY:

59188

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.606

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.669

Gnomad SAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.475

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.429

GnomAD4 exome

AF:

0.427

AC:

624484

AN:

1461460

Hom.:

137501

Cov.:

AF XY:

0.424

AC XY:

308494

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.121

Gnomad4 AMR exome

AF:

0.594

Gnomad4 ASJ exome

AF:

0.390

Gnomad4 EAS exome

AF:

0.639

Gnomad4 SAS exome

AF:

0.360

Gnomad4 FIN exome

AF:

0.463

Gnomad4 NFE exome

AF:

0.427

Gnomad4 OTH exome

AF:

0.428

GnomAD4 genome

AF:

0.362

AC:

55074

AN:

152000

Hom.:

11902

Cov.:

AF XY:

0.369

AC XY:

27420

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.137

Gnomad4 AMR

AF:

0.518

Gnomad4 ASJ

AF:

0.388

Gnomad4 EAS

AF:

0.673

Gnomad4 SAS

AF:

0.368

Gnomad4 FIN

AF:

0.476

Gnomad4 NFE

AF:

0.422

Gnomad4 OTH

AF:

0.378

Alfa

AF:

0.417

Hom.:

33759

Bravo

AF:

0.356

TwinsUK

AF:

0.432

AC:

1603

ALSPAC

AF:

0.439

AC:

1690

ESP6500AA

AF:

0.142

AC:

626

ESP6500EA

AF:

0.431

AC:

3706

ExAC

AF:

0.429

AC:

52128

Asia WGS

AF:

0.510

AC:

1772

AN:

3478

EpiCase

AF:

0.417

EpiControl

AF:

0.426

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	Genome-Nilou Lab	Aug 10, 2021	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not provided

Benign:2

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

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

0.12

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.000024

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.072

Sift

Benign

0.22

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.99

.;D

Vest4

0.038

MPC

0.34

ClinPred

0.025

GERP RS

3.5

Varity_R

0.075

gMVP

0.080

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