rs1463680

Variant names:

• chr3-45955269-G-A
• rs1463680
• NM_024513.4:c.3924C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-45955269-G-A
• chr3-45955269-G-C
• chr3-45955269-G-T

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.3924C>T​(p.Leu1308Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,613,656 control chromosomes in the GnomAD database, including 448,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47608 hom., cov: 32)
  • Exomes 𝑓: 0.74 (400595 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.877
• Publications: 33 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 (REVEL=0.009).
• BP6: Variant 3-45955269-G-A is Benign according to our data. Variant chr3-45955269-G-A is described in ClinVar as Benign. ClinVar VariationId is 261734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.877 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.3924C>T	p.Leu1308Leu	synonymous_variant	Exon 14 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.3924C>T	p.Leu1308Leu	synonymous_variant	Exon 14 of 18	1	NM_024513.4	ENSP00000296137.2
FYCO1	ENST00000438446.1	c.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6	5		ENSP00000398517.1
FYCO1	ENST00000433878.5	c.288C>T	p.Leu96Leu	synonymous_variant	Exon 2 of 7	2		ENSP00000388136.1
FYCO1	ENST00000438446.1	c.-64C>T		5_prime_UTR_variant	Exon 2 of 6	5		ENSP00000398517.1

Frequencies

GnomAD3 genomes AF: 0.786 AC: 119585 AN: 152048 Hom.: 47566 Cov.: 32

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.783

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.785

GnomAD2 exomes AF: 0.792 AC: 199149 AN: 251470 AF XY: 0.788

Gnomad AFR exome AF: 0.881

Gnomad AMR exome AF: 0.861

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.960

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.778

GnomAD4 exome AF: 0.737 AC: 1077763 AN: 1461492 Hom.: 400595 Cov.: 54 AF XY: 0.740 AC XY: 538148 AN XY: 727052

African (AFR) AF: 0.882 AC: 29533 AN: 33476

American (AMR) AF: 0.854 AC: 38207 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 20514 AN: 26134

East Asian (EAS) AF: 0.940 AC: 37309 AN: 39700

South Asian (SAS) AF: 0.850 AC: 73306 AN: 86238

European-Finnish (FIN) AF: 0.764 AC: 40790 AN: 53410

Middle Eastern (MID) AF: 0.817 AC: 4636 AN: 5676

European-Non Finnish (NFE) AF: 0.708 AC: 786965 AN: 1111756

Other (OTH) AF: 0.770 AC: 46503 AN: 60378

GnomAD4 genome AF: 0.787 AC: 119684 AN: 152164 Hom.: 47608 Cov.: 32 AF XY: 0.790 AC XY: 58777 AN XY: 74380

African (AFR) AF: 0.876 AC: 36349 AN: 41512

American (AMR) AF: 0.818 AC: 12498 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 2716 AN: 3470

East Asian (EAS) AF: 0.958 AC: 4964 AN: 5182

South Asian (SAS) AF: 0.870 AC: 4197 AN: 4826

European-Finnish (FIN) AF: 0.759 AC: 8032 AN: 10584

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.713 AC: 48460 AN: 67996

Other (OTH) AF: 0.788 AC: 1661 AN: 2108

Alfa AF: 0.743 Hom.: 49556

Bravo AF: 0.795

Asia WGS AF: 0.916 AC: 3185 AN: 3478

EpiCase AF: 0.726

EpiControl AF: 0.724

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:3

Aug 10, 2021

Genome-Nilou Lab

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.46
CADD	Benign	1.9
DANN	Benign	0.66
PhyloP100		-0.88
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1463680; hg19: chr3-45996761; COSMIC: COSV56114166;