3-45975359-A-T

Position:

• chr3-45975359-A-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.289-14T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,599,240 control chromosomes in the GnomAD database, including 148,401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11782 hom., cov: 32)
  • Exomes 𝑓: 0.43 (136619 hom.)
• Consequence: FYCO1 NM_024513.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.51

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 (BayesDel_noAF=-0.8).
• BP6: Variant 3-45975359-A-T is Benign according to our data. Variant chr3-45975359-A-T is described in ClinVar as [Benign]. Clinvar id is 261725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45975359-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.289-14T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.289-14T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54302 AN: 151978 Hom.: 11769 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.368

GnomAD3 exomes AF: 0.442 AC: 110744 AN: 250712 Hom.: 26634 AF XY: 0.435 AC XY: 58956 AN XY: 135492

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.605

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.669

Gnomad SAS exome AF: 0.359

Gnomad FIN exome AF: 0.475

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.428 AC: 619019 AN: 1447144 Hom.: 136619 Cov.: 27 AF XY: 0.425 AC XY: 306180 AN XY: 720976

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.593

Gnomad4 ASJ exome AF: 0.390

Gnomad4 EAS exome AF: 0.642

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.463

Gnomad4 NFE exome AF: 0.428

Gnomad4 OTH exome AF: 0.427

GnomAD4 genome AF: 0.357 AC: 54329 AN: 152096 Hom.: 11782 Cov.: 32 AF XY: 0.364 AC XY: 27086 AN XY: 74354

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.517

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.675

Gnomad4 SAS AF: 0.367

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.374

Alfa AF: 0.384 Hom.: 2241

Bravo AF: 0.350

Asia WGS AF: 0.512 AC: 1781 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 27, 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

Jul 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751552; hg19: chr3-46016851; COSMIC: COSV56114702;