rs13069079

Positions:

• chr3-45959378-G-A

Variant summary

Our verdict is Benign. Variant got -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:5
• Conservation: PhyloP100: -0.800

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
FYCO1	NM_024513.4	c.3587+15C>T		intron_variant		ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.3587+15C>T		intron_variant		1	NM_024513.4	P1

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

GnomAD3 exomes AF: 0.126 AC: 31461 AN: 249376 Hom.: 3154 AF XY: 0.141 AC XY: 19060 AN XY: 135004

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 SAS exome AF: 0.347

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

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0655

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.00204

Gnomad4 SAS exome AF: 0.343

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.118

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

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.0662

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.00329

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.0928

Alfa AF: 0.124 Hom.: 782

Bravo AF: 0.0722

Asia WGS AF: 0.172 AC: 599 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.18
DANN	Benign	0.40

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

Other links and lift over

dbSNP: rs13069079; hg19: chr3-46000870;