3-45918708-C-T

Position:

• chr3-45918708-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_024513.4(FYCO1):​c.*3057G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 152,278 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: FYCO1 NM_024513.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.270

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00474 (722/152278) while in subpopulation NFE AF= 0.00735 (500/68016). AF 95% confidence interval is 0.00682. There are 2 homozygotes in gnomad4. There are 375 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.*3057G>A		3_prime_UTR_variant	18/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.*3057G>A		3_prime_UTR_variant	18/18	1	NM_024513.4	P1
FYCO1	ENST00000433878.5	c.*2710G>A		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 722 AN: 152160 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00924

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00574

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00474 AC: 722 AN: 152278 Hom.: 2 Cov.: 32 AF XY: 0.00504 AC XY: 375 AN XY: 74460

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00924

Gnomad4 NFE AF: 0.00735

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00487 Hom.: 0

Bravo AF: 0.00414

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 18 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.81
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs537667165; hg19: chr3-45960200;