NM_024513.4:c.-113+5257G>A

Variant names:

• chr3-45990465-C-T
• rs2133660
• NM_024513.4:c.-113+5257G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024513.4(FYCO1):​c.-113+5257G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 152,014 control chromosomes in the GnomAD database, including 26,122 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (26122 hom., cov: 32)
• Consequence: FYCO1 NM_024513.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.933
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024513.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	NM_024513.4	MANE Select	c.-113+5257G>A		intron	N/A	NP_078789.2
	FYCO1	NM_001386421.1		c.-196-5230G>A		intron	N/A	NP_001373350.1
	FYCO1	NM_001386423.1		c.-113+5257G>A		intron	N/A	NP_001373352.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.-113+5257G>A		intron	N/A	ENSP00000296137.2
	FYCO1	ENST00000471739.1	TSL:4	n.103+5257G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84770 AN: 151896 Hom.: 26109 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.954

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.602

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.558 AC: 84819 AN: 152014 Hom.: 26122 Cov.: 32 AF XY: 0.562 AC XY: 41758 AN XY: 74302

African (AFR) AF: 0.298 AC: 12348 AN: 41434

American (AMR) AF: 0.719 AC: 10979 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2129 AN: 3468

East Asian (EAS) AF: 0.954 AC: 4947 AN: 5184

South Asian (SAS) AF: 0.527 AC: 2539 AN: 4822

European-Finnish (FIN) AF: 0.652 AC: 6882 AN: 10552

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43167 AN: 67964

Other (OTH) AF: 0.605 AC: 1278 AN: 2112

Alfa AF: 0.607 Hom.: 15402

Bravo AF: 0.557

Asia WGS AF: 0.711 AC: 2472 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.24
DANN	Benign	0.39
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2133660; hg19: chr3-46031957;