rs3796375

Variant names:

• chr3-45967298-G-A
• rs3796375
• NM_024513.4:c.2036C>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.2036C>T​(p.Ala679Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,613,460 control chromosomes in the GnomAD database, including 149,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A679A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (11902 hom., cov: 32)
  • Exomes 𝑓: 0.43 (137501 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.12
• Publications: 47 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 (MetaRNN=2.427137E-5).
• BP6: Variant 3-45967298-G-A is Benign according to our data. Variant chr3-45967298-G-A is described in ClinVar as Benign. ClinVar VariationId is 261722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.2036C>T	p.Ala679Val	missense_variant	Exon 8 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.2036C>T	p.Ala679Val	missense_variant	Exon 8 of 18	1	NM_024513.4	ENSP00000296137.2

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55046 AN: 151882 Hom.: 11889 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.372

GnomAD2 exomes AF: 0.443 AC: 111217 AN: 250966 AF XY: 0.436

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.606

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.669

Gnomad FIN exome AF: 0.475

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.427 AC: 624484 AN: 1461460 Hom.: 137501 Cov.: 73 AF XY: 0.424 AC XY: 308494 AN XY: 727036

African (AFR) AF: 0.121 AC: 4057 AN: 33474

American (AMR) AF: 0.594 AC: 26580 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10181 AN: 26132

East Asian (EAS) AF: 0.639 AC: 25349 AN: 39694

South Asian (SAS) AF: 0.360 AC: 31020 AN: 86256

European-Finnish (FIN) AF: 0.463 AC: 24590 AN: 53134

Middle Eastern (MID) AF: 0.348 AC: 2005 AN: 5762

European-Non Finnish (NFE) AF: 0.427 AC: 474877 AN: 1111904

Other (OTH) AF: 0.428 AC: 25825 AN: 60384

GnomAD4 genome AF: 0.362 AC: 55074 AN: 152000 Hom.: 11902 Cov.: 32 AF XY: 0.369 AC XY: 27420 AN XY: 74308

African (AFR) AF: 0.137 AC: 5680 AN: 41498

American (AMR) AF: 0.518 AC: 7915 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1348 AN: 3470

East Asian (EAS) AF: 0.673 AC: 3465 AN: 5148

South Asian (SAS) AF: 0.368 AC: 1770 AN: 4816

European-Finnish (FIN) AF: 0.476 AC: 5032 AN: 10566

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28645 AN: 67924

Other (OTH) AF: 0.378 AC: 797 AN: 2110

Alfa AF: 0.414 Hom.: 61730

Bravo AF: 0.356

TwinsUK AF: 0.432 AC: 1603

ALSPAC AF: 0.439 AC: 1690

ESP6500AA AF: 0.142 AC: 626

ESP6500EA AF: 0.431 AC: 3706

ExAC AF: 0.429 AC: 52128

Asia WGS AF: 0.510 AC: 1772 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.426

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:3

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. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Apr 02, 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.000024	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		3.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.072
Sift	Benign	0.22	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.99	.;D
Vest4		0.038
MPC		0.34
ClinPred		0.025	T
GERP RS		3.5
Varity_R		0.075
gMVP		0.080
Mutation Taster		=99/1	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: rs3796375; hg19: chr3-46008790; COSMIC: COSV56114179;