rs41289612

chr3-45923698-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024513.4(FYCO1):c.4319C>T(p.Thr1440Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00554 in 1,614,120 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (34 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.03

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014971375).
• BP6: Variant 3-45923698-G-A is Benign according to our data. Variant chr3-45923698-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345495.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}. Variant chr3-45923698-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00432 (658/152330) while in subpopulation AMR AF= 0.00732 (112/15310). AF 95% confidence interval is 0.00622. There are 1 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.4319C>T	p.Thr1440Ile	missense_variant	17/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.4319C>T	p.Thr1440Ile	missense_variant	17/18	1	NM_024513.4	P1
FYCO1	ENST00000433878.5	c.686C>T	p.Thr229Ile	missense_variant	5/7	2
FYCO1	ENST00000438446.1	c.332C>T	p.Thr111Ile	missense_variant	5/6	5

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 659 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00659

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00355 AC: 892 AN: 251478 Hom.: 2 AF XY: 0.00350 AC XY: 476 AN XY: 135912

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00567 AC: 8289 AN: 1461790 Hom.: 34 Cov.: 31 AF XY: 0.00552 AC XY: 4014 AN XY: 727194

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.00672

Gnomad4 OTH exome AF: 0.00540

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74496

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00657

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00472 Hom.: 0

Bravo AF: 0.00443

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00344 AC: 418

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00539

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 18 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 27, 2020	- -
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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	FYCO1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	See Variant Classification Assertion Criteria. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.4319C>T (p.T1440I) alteration is located in exon 17 (coding exon 16) of the FYCO1 gene. This alteration results from a C to T substitution at nucleotide position 4319, causing the threonine (T) at amino acid position 1440 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.34
MVP		0.38
MPC		0.17
ClinPred		0.012	T
GERP RS		3.2
Varity_R		0.020
gMVP		0.26

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: rs41289612; hg19: chr3-45965190;