rs41289618

Variant names:

• chr3-45958418-T-C
• rs41289618
• NM_024513.4:c.3789A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024513.4(FYCO1):​c.3789A>G​(p.Thr1263Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,612,242 control chromosomes in the GnomAD database, including 886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (76 hom., cov: 33)
  • Exomes 𝑓: 0.032 (810 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.140

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=-0.87).
• BP6: Variant 3-45958418-T-C is Benign according to our data. Variant chr3-45958418-T-C is described in ClinVar as [Benign]. Clinvar id is 345501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45958418-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0258 (3935/152350) while in subpopulation NFE AF= 0.0386 (2623/68028). AF 95% confidence interval is 0.0373. There are 76 homozygotes in gnomad4. There are 1890 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 76 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.3789A>G	p.Thr1263Thr	synonymous_variant	Exon 13 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.3789A>G	p.Thr1263Thr	synonymous_variant	Exon 13 of 18	1	NM_024513.4	ENSP00000296137.2
FYCO1	ENST00000433878.5	c.153A>G	p.Thr51Thr	synonymous_variant	Exon 1 of 7	2		ENSP00000388136.1
FYCO1	ENST00000438446.1	c.-199A>G		5_prime_UTR_variant	Exon 1 of 6	5		ENSP00000398517.1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3938 AN: 152232 Hom.: 76 Cov.: 33

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.0396

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0386

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0287 AC: 7143 AN: 249260 Hom.: 126 AF XY: 0.0289 AC XY: 3893 AN XY: 134906

Gnomad AFR exome AF: 0.00520

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0309

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00599

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0417

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0317 AC: 46206 AN: 1459892 Hom.: 810 Cov.: 32 AF XY: 0.0312 AC XY: 22693 AN XY: 726226

Gnomad4 AFR exome AF: 0.00464

Gnomad4 AMR exome AF: 0.0253

Gnomad4 ASJ exome AF: 0.0320

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00721

Gnomad4 FIN exome AF: 0.0421

Gnomad4 NFE exome AF: 0.0353

Gnomad4 OTH exome AF: 0.0292

GnomAD4 genome AF: 0.0258 AC: 3935 AN: 152350 Hom.: 76 Cov.: 33 AF XY: 0.0254 AC XY: 1890 AN XY: 74500

Gnomad4 AFR AF: 0.00625

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00579

Gnomad4 FIN AF: 0.0396

Gnomad4 NFE AF: 0.0386

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0326 Hom.: 59

Bravo AF: 0.0244

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0403

EpiControl AF: 0.0377

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:2

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. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Apr 14, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.37

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: rs41289618; hg19: chr3-45999910;