rs33910087

chr3-45967995-G-Achr3-45967995-G-Cchr3-45967995-G-T

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.1339C>T(p.Arg447Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,916 control chromosomes in the GnomAD database, including 13,793 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R447H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.092 (1004 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12789 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.816

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=0.002291739).
• BP6: Variant 3-45967995-G-A is Benign according to our data. Variant chr3-45967995-G-A is described in ClinVar as [Benign]. Clinvar id is 261720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45967995-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.1339C>T	p.Arg447Cys	missense_variant	8/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.1339C>T	p.Arg447Cys	missense_variant	8/18	1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14006 AN: 151952 Hom.: 1005 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00367

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0943

GnomAD3 exomes AF: 0.125 AC: 31541 AN: 251438 Hom.: 3091 AF XY: 0.140 AC XY: 19032 AN XY: 135900

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.0613

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.00272

Gnomad SAS exome AF: 0.340

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.115 AC: 168692 AN: 1461846 Hom.: 12789 Cov.: 75 AF XY: 0.124 AC XY: 89921 AN XY: 727224

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.0633

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.0921 AC: 13999 AN: 152070 Hom.: 1004 Cov.: 32 AF XY: 0.0979 AC XY: 7280 AN XY: 74340

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00368

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.0953

Alfa AF: 0.103 Hom.: 1410

Bravo AF: 0.0756

TwinsUK AF: 0.102 AC: 378

ALSPAC AF: 0.101 AC: 390

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.110 AC: 948

ExAC AF: 0.128 AC: 15483

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.113

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	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	Genome-Nilou Lab	Aug 10, 2021	- -
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

May 10, 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	0.076
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	7.6
Dann	Benign	0.92
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.059
Sift	Benign	0.048	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.95	.;P
Vest4		0.051
MPC		0.22
ClinPred		0.0036	T
GERP RS		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.079

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: rs33910087; hg19: chr3-46009487; COSMIC: COSV56115935;