rs34801630

chr3-45966354-C-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.2980G>A(p.Glu994Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0188 in 1,614,204 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (481 hom., cov: 33)
  • Exomes 𝑓: 0.015 (559 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.82

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=0.001597017).
• BP6: Variant 3-45966354-C-T is Benign according to our data. Variant chr3-45966354-C-T is described in ClinVar as [Benign]. Clinvar id is 261726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45966354-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.2980G>A	p.Glu994Lys	missense_variant	8/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.2980G>A	p.Glu994Lys	missense_variant	8/18	1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7684 AN: 152234 Hom.: 478 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0415

GnomAD3 exomes AF: 0.0223 AC: 5581 AN: 250090 Hom.: 227 AF XY: 0.0185 AC XY: 2503 AN XY: 135272

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.0155 AC: 22642 AN: 1461852 Hom.: 559 Cov.: 37 AF XY: 0.0145 AC XY: 10538 AN XY: 727230

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0322

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00373

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0190

GnomAD4 genome AF: 0.0505 AC: 7701 AN: 152352 Hom.: 481 Cov.: 33 AF XY: 0.0480 AC XY: 3576 AN XY: 74496

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.0314

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.0182 Hom.: 145

Bravo AF: 0.0581

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.146 AC: 643

ESP6500EA AF: 0.0123 AC: 106

ExAC AF: 0.0245 AC: 2979

Asia WGS AF: 0.00982 AC: 35 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0116

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:2

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	Invitae	Jan 21, 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

Apr 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	26
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	0.000022	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.23
MPC		0.61
ClinPred		0.029	T
GERP RS		5.5
Varity_R		0.29
gMVP		0.27

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: rs34801630; hg19: chr3-46007846;