3-45918267-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024513.4(FYCO1):c.*3498A>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 0.366 in 152,310 control chromosomes in the GnomAD database, including 11,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11376 hom., cov: 32)
  • Exomes 𝑓: 0.39 (15 hom.)
• Consequence: FYCO1 NM_024513.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.328

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-45918267-T-C is Benign according to our data. Variant chr3-45918267-T-C is described in ClinVar as [Benign]. Clinvar id is 345439.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.*3498A>G		3_prime_UTR_variant	18/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.*3498A>G		3_prime_UTR_variant	18/18	1	NM_024513.4	P1
FYCO1	ENST00000433878.5	c.*3151A>G		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55664 AN: 151954 Hom.: 11360 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.375

GnomAD4 exome AF: 0.387 AC: 92 AN: 238 Hom.: 15 Cov.: 0 AF XY: 0.390 AC XY: 57 AN XY: 146

Gnomad4 FIN exome AF: 0.389

Gnomad4 NFE exome AF: 0.250

GnomAD4 genome AF: 0.366 AC: 55709 AN: 152072 Hom.: 11376 Cov.: 32 AF XY: 0.372 AC XY: 27650 AN XY: 74326

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.515

Gnomad4 ASJ AF: 0.388

Gnomad4 EAS AF: 0.650

Gnomad4 SAS AF: 0.363

Gnomad4 FIN AF: 0.435

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.380

Alfa AF: 0.373 Hom.: 6483

Bravo AF: 0.365

Asia WGS AF: 0.517 AC: 1799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 18 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	5.9
Dann	Benign	0.85

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: rs7129; hg19: chr3-45959759;