rs34147726

Variant names:

• chr3-45968128-C-T
• rs34147726
• NM_024513.4:c.1206G>A

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.1206G>A​(p.Glu402Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,614,100 control chromosomes in the GnomAD database, including 3,841 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (2053 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (1788 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.150

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 3-45968128-C-T is Benign according to our data. Variant chr3-45968128-C-T is described in ClinVar as [Benign]. Clinvar id is 261718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.1206G>A	p.Glu402Glu	synonymous_variant	Exon 8 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.1206G>A	p.Glu402Glu	synonymous_variant	Exon 8 of 18	1	NM_024513.4	ENSP00000296137.2

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13428 AN: 152130 Hom.: 2052 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0583

GnomAD3 exomes AF: 0.0223 AC: 5610 AN: 251380 Hom.: 809 AF XY: 0.0161 AC XY: 2186 AN XY: 135878

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00855 AC: 12493 AN: 1461852 Hom.: 1788 Cov.: 79 AF XY: 0.00728 AC XY: 5296 AN XY: 727222

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0883 AC: 13446 AN: 152248 Hom.: 2053 Cov.: 32 AF XY: 0.0847 AC XY: 6304 AN XY: 74464

Gnomad4 AFR AF: 0.309

Gnomad4 AMR AF: 0.0292

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0400 Hom.: 448

Bravo AF: 0.102

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

May 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.5
DANN	Benign	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: rs34147726; hg19: chr3-46009620;