rs3796376

chr3-45967999-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024513.4(FYCO1):c.1335G>A(p.Leu445=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,614,032 control chromosomes in the GnomAD database, including 30,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2226 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27909 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.103

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 3-45967999-C-T is Benign according to our data. Variant chr3-45967999-C-T is described in ClinVar as [Benign]. Clinvar id is 261719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45967999-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.1335G>A	p.Leu445=	synonymous_variant	8/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.1335G>A	p.Leu445=	synonymous_variant	8/18	1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23996 AN: 152042 Hom.: 2223 Cov.: 32

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.183 AC: 46021 AN: 251450 Hom.: 4526 AF XY: 0.186 AC XY: 25305 AN XY: 135906

Gnomad AFR exome AF: 0.0604

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.191 AC: 279749 AN: 1461872 Hom.: 27909 Cov.: 81 AF XY: 0.191 AC XY: 139213 AN XY: 727236

Gnomad4 AFR exome AF: 0.0586

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.192

GnomAD4 genome AF: 0.158 AC: 23997 AN: 152160 Hom.: 2226 Cov.: 32 AF XY: 0.157 AC XY: 11674 AN XY: 74374

Gnomad4 AFR AF: 0.0641

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.190

Alfa AF: 0.179 Hom.: 1274

Bravo AF: 0.159

Asia WGS AF: 0.189 AC: 655 AN: 3478

EpiCase AF: 0.208

EpiControl AF: 0.202

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 26, 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

Mar 24, 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
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.58
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3796376; hg19: chr3-46009491; COSMIC: COSV56113661;