3-45962243-C-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.3419G>A(p.Arg1140Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,124 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (112 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.59

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=0.008017093).
• BP6: Variant 3-45962243-C-T is Benign according to our data. Variant chr3-45962243-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45962243-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00821 (1250/152310) while in subpopulation NFE AF= 0.0119 (810/68018). AF 95% confidence interval is 0.0112. There are 7 homozygotes in gnomad4. There are 586 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.3419G>A	p.Arg1140Gln	missense_variant	11/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.3419G>A	p.Arg1140Gln	missense_variant	11/18	1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1250 AN: 152192 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00886

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0107 AC: 2699 AN: 251452 Hom.: 28 AF XY: 0.0102 AC XY: 1381 AN XY: 135900

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00800

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0108 AC: 15854 AN: 1461814 Hom.: 112 Cov.: 32 AF XY: 0.0106 AC XY: 7697 AN XY: 727218

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.0208

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00814

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00889

GnomAD4 genome AF: 0.00821 AC: 1250 AN: 152310 Hom.: 7 Cov.: 32 AF XY: 0.00787 AC XY: 586 AN XY: 74480

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.00886

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00964 Hom.: 14

Bravo AF: 0.00861

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.0104 AC: 1266

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00987

EpiControl AF: 0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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 18, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	.;D
Vest4		0.66
MPC		0.72
ClinPred		0.044	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.76

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: rs41289620; hg19: chr3-46003735;