rs146711260

chr3-45967895-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024513.4(FYCO1):c.1439C>T(p.Thr480Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,614,080 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.803

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 (MetaRNN=0.002865553).
• BP6: Variant 3-45967895-G-A is Benign according to our data. Variant chr3-45967895-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 468439.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 = 0.00244 (372/152222) while in subpopulation AFR AF= 0.00854 (355/41558). AF 95% confidence interval is 0.00781. There are 2 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.1439C>T	p.Thr480Met	missense_variant	8/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.1439C>T	p.Thr480Met	missense_variant	8/18	1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 372 AN: 152104 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000637 AC: 160 AN: 251246 Hom.: 1 AF XY: 0.000493 AC XY: 67 AN XY: 135792

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000236 AC: 345 AN: 1461858 Hom.: 0 Cov.: 74 AF XY: 0.000213 AC XY: 155 AN XY: 727230

Gnomad4 AFR exome AF: 0.00750

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74436

Gnomad4 AFR AF: 0.00854

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000439 Hom.: 0

Bravo AF: 0.00272

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

FYCO1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	2.8
Dann	Benign	0.82
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.49	N;N
REVEL	Benign	0.014
Sift	Benign	0.078	T;T
Sift4G	Uncertain	0.052	T;T
Polyphen		0.016	.;B
Vest4		0.082
MVP		0.17
MPC		0.16
ClinPred		0.0027	T
GERP RS		-0.88
Varity_R		0.015
gMVP		0.038

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: rs146711260; hg19: chr3-46009387;