rs35678722

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024513.4(FYCO1):c.4265C>T(p.Thr1422Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000819 in 1,613,534 control chromosomes in the GnomAD database, including 7 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 0.0037 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 3 hom. )

Consequence

FYCO1
NM_024513.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.60

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=0.00589177).

BP6

Variant 3-45923752-G-A is Benign according to our data. Variant chr3-45923752-G-A is described in ClinVar as [Benign]. Clinvar id is 468449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00365 (556/152260) while in subpopulation AFR AF= 0.0126 (524/41538). AF 95% confidence interval is 0.0117. There are 4 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4 linkuse as main transcript	c.4265C>T	p.Thr1422Met	missense_variant	17/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7 linkuse as main transcript	c.4265C>T	p.Thr1422Met	missense_variant	17/18	1	NM_024513.4	P1	Q9BQS8-1
FYCO1	ENST00000433878.5 linkuse as main transcript	c.632C>T	p.Thr211Met	missense_variant	5/7	2
FYCO1	ENST00000438446.1 linkuse as main transcript	c.278C>T	p.Thr93Met	missense_variant	5/6	5

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

553

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00105

AC:

264

AN:

251460

Hom.:

AF XY:

0.000706

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000524

AC:

766

AN:

1461274

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

326

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0128

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000196

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.00365

AC:

556

AN:

152260

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0126

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000640

Hom.:

Bravo

AF:

0.00415

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00116

AC:

141

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 18

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Dec 09, 2023	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

FYCO1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.92

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.78

T;T;D

MetaRNN

Benign

0.0059

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.67

N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.080

N;N;N

REVEL

Benign

0.025

Sift

Benign

0.23

T;T;T

Sift4G

Benign

0.32

T;T;T

Polyphen

0.20

.;B;.

Vest4

0.30

MVP

0.30

MPC

0.18

ClinPred

0.0054

GERP RS

2.2

Varity_R

0.015

gMVP

0.21

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