3-45967895-G-A

Variant names:

• chr3-45967895-G-A
• rs146711260
• NM_024513.4:c.1439C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024513.4(FYCO1):​c.1439C>T​(p.Thr480Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,614,080 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.803
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002865553).
• BP6: Variant 3-45967895-G-A is Benign according to our data. Variant chr3-45967895-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468439.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00244 (372/152222) while in subpopulation AFR AF = 0.00854 (355/41558). AF 95% confidence interval is 0.00781. There are 2 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	NM_024513.4	MANE Select	c.1439C>T	p.Thr480Met	missense	Exon 8 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.1439C>T	p.Thr480Met	missense	Exon 9 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.1439C>T	p.Thr480Met	missense	Exon 8 of 18	NP_001373351.1	Q9BQS8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.1439C>T	p.Thr480Met	missense	Exon 8 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.1439C>T	p.Thr480Met	missense	Exon 9 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.1439C>T	p.Thr480Met	missense	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 372 AN: 152104 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000637 AC: 160 AN: 251246 AF XY: 0.000493

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000236 AC: 345 AN: 1461858 Hom.: 0 Cov.: 74 AF XY: 0.000213 AC XY: 155 AN XY: 727230

African (AFR) AF: 0.00750 AC: 251 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1112004

Other (OTH) AF: 0.000447 AC: 27 AN: 60396

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74436

African (AFR) AF: 0.00854 AC: 355 AN: 41558

American (AMR) AF: 0.000653 AC: 10 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.000929 Hom.: 0

Bravo AF: 0.00272

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Cataract 18 (3)
-	-	1	FYCO1-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.8
DANN	Benign	0.82
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.80
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.014
Sift	Benign	0.078	T
Sift4G	Uncertain	0.052	T
Polyphen		0.016	B
Vest4		0.082
MVP		0.17
MPC		0.16
ClinPred		0.0027	T
GERP RS		-0.88
Varity_R		0.015
gMVP		0.038
Mutation Taster		=100/0	polymorphism

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: rs146711260; hg19: chr3-46009387;