chr3-45959378-G-A

Variant names:

• chr3-45959378-G-A
• rs13069079
• NM_024513.4:c.3587+15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024513.4(FYCO1):​c.3587+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,428 control chromosomes in the GnomAD database, including 14,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1011 hom., cov: 33)
  • Exomes 𝑓: 0.12 (13031 hom.)
• Consequence: FYCO1 NM_024513.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.800
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 3-45959378-G-A is Benign according to our data. Variant chr3-45959378-G-A is described in ClinVar as Benign. ClinVar VariationId is 261732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.3587+15C>T		intron_variant	Intron 12 of 17	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.3587+15C>T		intron_variant	Intron 12 of 17	1	NM_024513.4	ENSP00000296137.2

Frequencies

GnomAD3 genomes AF: 0.0891 AC: 13559 AN: 152098 Hom.: 1013 Cov.: 33

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.0664

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0919

GnomAD2 exomes AF: 0.126 AC: 31461 AN: 249376 AF XY: 0.141

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.0641

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.00256

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.116 AC: 169272 AN: 1461212 Hom.: 13031 Cov.: 33 AF XY: 0.124 AC XY: 90334 AN XY: 726884

African (AFR) AF: 0.0160 AC: 534 AN: 33470

American (AMR) AF: 0.0655 AC: 2929 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4717 AN: 26134

East Asian (EAS) AF: 0.00204 AC: 81 AN: 39700

South Asian (SAS) AF: 0.343 AC: 29563 AN: 86250

European-Finnish (FIN) AF: 0.144 AC: 7620 AN: 52986

Middle Eastern (MID) AF: 0.189 AC: 1090 AN: 5766

European-Non Finnish (NFE) AF: 0.104 AC: 115616 AN: 1111814

Other (OTH) AF: 0.118 AC: 7122 AN: 60370

GnomAD4 genome AF: 0.0890 AC: 13550 AN: 152216 Hom.: 1011 Cov.: 33 AF XY: 0.0950 AC XY: 7069 AN XY: 74420

African (AFR) AF: 0.0177 AC: 736 AN: 41546

American (AMR) AF: 0.0662 AC: 1013 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3472

East Asian (EAS) AF: 0.00329 AC: 17 AN: 5164

South Asian (SAS) AF: 0.350 AC: 1692 AN: 4828

European-Finnish (FIN) AF: 0.145 AC: 1539 AN: 10588

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7466 AN: 68000

Other (OTH) AF: 0.0928 AC: 196 AN: 2112

Alfa AF: 0.121 Hom.: 824

Bravo AF: 0.0722

Asia WGS AF: 0.172 AC: 599 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:3

Jan 22, 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

Aug 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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	-0.96
CADD	Benign	0.18
DANN	Benign	0.40
PhyloP100		-0.80
Mutation Taster		=100/0	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: rs13069079; hg19: chr3-46000870;