rs4682801

Variant names:

• chr3-45979726-G-T
• rs4682801
• NM_024513.4:c.267C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024513.4(FYCO1):​c.267C>A​(p.Arg89Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 1,613,298 control chromosomes in the GnomAD database, including 484,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (39463 hom., cov: 33)
  • Exomes 𝑓: 0.78 (445142 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.344
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• cataract 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-45979726-G-T is Benign according to our data. Variant chr3-45979726-G-T is described in ClinVar as Benign. ClinVar VariationId is 261723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.344 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.267C>A	p.Arg89Arg	synonymous_variant	Exon 4 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.267C>A	p.Arg89Arg	synonymous_variant	Exon 4 of 18	1	NM_024513.4	ENSP00000296137.2

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106144 AN: 152014 Hom.: 39435 Cov.: 33

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.751

GnomAD2 exomes AF: 0.808 AC: 203219 AN: 251496 AF XY: 0.815

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 0.846

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.810

Gnomad NFE exome AF: 0.774

Gnomad OTH exome AF: 0.814

GnomAD4 exome AF: 0.776 AC: 1134220 AN: 1461166 Hom.: 445142 Cov.: 50 AF XY: 0.781 AC XY: 568002 AN XY: 726918

African (AFR) AF: 0.423 AC: 14168 AN: 33464

American (AMR) AF: 0.892 AC: 39903 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 22085 AN: 26122

East Asian (EAS) AF: 0.999 AC: 39669 AN: 39690

South Asian (SAS) AF: 0.899 AC: 77580 AN: 86252

European-Finnish (FIN) AF: 0.806 AC: 43002 AN: 53364

Middle Eastern (MID) AF: 0.882 AC: 5084 AN: 5766

European-Non Finnish (NFE) AF: 0.760 AC: 845029 AN: 1111442

Other (OTH) AF: 0.790 AC: 47700 AN: 60346

GnomAD4 genome AF: 0.698 AC: 106218 AN: 152132 Hom.: 39463 Cov.: 33 AF XY: 0.708 AC XY: 52671 AN XY: 74368

African (AFR) AF: 0.430 AC: 17798 AN: 41438

American (AMR) AF: 0.841 AC: 12861 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2918 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5170 AN: 5174

South Asian (SAS) AF: 0.909 AC: 4391 AN: 4832

European-Finnish (FIN) AF: 0.809 AC: 8569 AN: 10598

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.766 AC: 52065 AN: 68006

Other (OTH) AF: 0.754 AC: 1593 AN: 2112

Alfa AF: 0.749 Hom.: 68764

Bravo AF: 0.687

Asia WGS AF: 0.939 AC: 3262 AN: 3478

EpiCase AF: 0.781

EpiControl AF: 0.781

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.99
DANN	Benign	0.72
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4682801; hg19: chr3-46021218; COSMIC: COSV108101686; COSMIC: COSV108101686;