rs143704916

chr3-45967860-G-Achr3-45967860-G-T

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.1474C>T(p.Arg492Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,613,890 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (14 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.06

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=0.004735142).
• BP6: Variant 3-45967860-G-A is Benign according to our data. Variant chr3-45967860-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 345523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45967860-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00257 (391/152074) while in subpopulation AMR AF= 0.00773 (118/15268). AF 95% confidence interval is 0.0066. There are 2 homozygotes in gnomad4. There are 183 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.1474C>T	p.Arg492Trp	missense_variant	8/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.1474C>T	p.Arg492Trp	missense_variant	8/18	1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 151956 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00774

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00352

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00229 AC: 574 AN: 251070 Hom.: 5 AF XY: 0.00214 AC XY: 291 AN XY: 135702

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00254 AC: 3712 AN: 1461816 Hom.: 14 Cov.: 74 AF XY: 0.00244 AC XY: 1776 AN XY: 727210

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00257 AC: 391 AN: 152074 Hom.: 2 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74344

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.00773

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00298 Hom.: 3

Bravo AF: 0.00335

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00265 AC: 322

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	FYCO1: BP4 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2021	- -

FYCO1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2020

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.073
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	.;D
Vest4		0.27
MVP		0.30
MPC		0.38
ClinPred		0.021	T
GERP RS		3.6
Varity_R		0.081
gMVP		0.19

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: rs143704916; hg19: chr3-46009352;