3-45939277-C-T

Variant names:

• chr3-45939277-C-T
• rs936938
• NM_024513.4:c.3945-2734G>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.3945-2734G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 152,106 control chromosomes in the GnomAD database, including 11,800 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 0.38 (11800 hom., cov: 33)
• Consequence: FYCO1 NM_024513.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.146
• Publications: 6 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.3945-2734G>A		intron_variant	Intron 14 of 17	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.3945-2734G>A		intron_variant	Intron 14 of 17	1	NM_024513.4	ENSP00000296137.2
FYCO1	ENST00000433878.5	c.309-2734G>A		intron_variant	Intron 2 of 6	2		ENSP00000388136.1
FYCO1	ENST00000438446.1	c.-43-2734G>A		intron_variant	Intron 2 of 5	5		ENSP00000398517.1
FYCO1	ENST00000691721.1	n.77+50G>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57423 AN: 151988 Hom.: 11783 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.378 AC: 57473 AN: 152106 Hom.: 11800 Cov.: 33 AF XY: 0.384 AC XY: 28552 AN XY: 74334

African (AFR) AF: 0.254 AC: 10551 AN: 41488

American (AMR) AF: 0.519 AC: 7928 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1339 AN: 3470

East Asian (EAS) AF: 0.661 AC: 3424 AN: 5180

South Asian (SAS) AF: 0.362 AC: 1744 AN: 4822

European-Finnish (FIN) AF: 0.437 AC: 4617 AN: 10566

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.392 AC: 26633 AN: 67978

Other (OTH) AF: 0.388 AC: 819 AN: 2112

Alfa AF: 0.368 Hom.: 1418

Bravo AF: 0.378

Asia WGS AF: 0.520 AC: 1809 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.30
PhyloP100		0.15
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: rs936938; hg19: chr3-45980769;