3-45921260-T-C

Variant names:

• chr3-45921260-T-C
• rs7652331
• NM_024513.4:c.*505A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024513.4(FYCO1):​c.*505A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 210,050 control chromosomes in the GnomAD database, including 57,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43721 hom., cov: 33)
  • Exomes 𝑓: 0.68 (14079 hom.)
• Consequence: FYCO1 NM_024513.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.16
• Publications: 36 publications found

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]

FYCO1 Gene-Disease associations (from GenCC):

• cataract 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 3-45921260-T-C is Benign according to our data. Variant chr3-45921260-T-C is described in ClinVar as Benign. ClinVar VariationId is 345484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.*505A>G		3_prime_UTR_variant	Exon 18 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.*505A>G		3_prime_UTR_variant	Exon 18 of 18	1	NM_024513.4	ENSP00000296137.2
FYCO1	ENST00000433878.5	c.*505A>G		3_prime_UTR_variant	Exon 6 of 7	2		ENSP00000388136.1

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113453 AN: 152100 Hom.: 43658 Cov.: 33

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.821

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.753

GnomAD4 exome AF: 0.683 AC: 39525 AN: 57832 Hom.: 14079 Cov.: 0 AF XY: 0.677 AC XY: 20423 AN XY: 30162

African (AFR) AF: 0.911 AC: 1930 AN: 2118

American (AMR) AF: 0.828 AC: 3116 AN: 3762

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 819 AN: 1260

East Asian (EAS) AF: 0.998 AC: 3847 AN: 3856

South Asian (SAS) AF: 0.562 AC: 3884 AN: 6910

European-Finnish (FIN) AF: 0.657 AC: 1267 AN: 1928

Middle Eastern (MID) AF: 0.712 AC: 141 AN: 198

European-Non Finnish (NFE) AF: 0.645 AC: 22546 AN: 34934

Other (OTH) AF: 0.689 AC: 1975 AN: 2866

GnomAD4 genome AF: 0.746 AC: 113579 AN: 152218 Hom.: 43721 Cov.: 33 AF XY: 0.744 AC XY: 55368 AN XY: 74418

African (AFR) AF: 0.908 AC: 37758 AN: 41568

American (AMR) AF: 0.822 AC: 12576 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 2306 AN: 3470

East Asian (EAS) AF: 0.996 AC: 5154 AN: 5176

South Asian (SAS) AF: 0.575 AC: 2772 AN: 4822

European-Finnish (FIN) AF: 0.636 AC: 6727 AN: 10570

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44145 AN: 67982

Other (OTH) AF: 0.754 AC: 1596 AN: 2116

Alfa AF: 0.704 Hom.: 72373

Bravo AF: 0.775

Asia WGS AF: 0.792 AC: 2753 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:1

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:1

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	-0.97
CADD	Benign	0.077
DANN	Benign	0.26
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7652331; hg19: chr3-45962752;