rs41289612

Variant names:

• chr3-45923698-G-A
• rs41289612
• NM_024513.4:c.4319C>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.4319C>T​(p.Thr1440Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00554 in 1,614,120 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (34 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.03
• 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=0.014971375).
• BP6: Variant 3-45923698-G-A is Benign according to our data. Variant chr3-45923698-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 345495.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00432 (658/152330) while in subpopulation AMR AF = 0.00732 (112/15310). AF 95% confidence interval is 0.00622. There are 1 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 34 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.4319C>T	p.Thr1440Ile	missense	Exon 17 of 18	NP_078789.2
	FYCO1	NM_001386421.1		c.4319C>T	p.Thr1440Ile	missense	Exon 18 of 19	NP_001373350.1
	FYCO1	NM_001386422.1		c.4319C>T	p.Thr1440Ile	missense	Exon 17 of 18	NP_001373351.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.4319C>T	p.Thr1440Ile	missense	Exon 17 of 18	ENSP00000296137.2
	FYCO1	ENST00000874259.1		c.4319C>T	p.Thr1440Ile	missense	Exon 18 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.4319C>T	p.Thr1440Ile	missense	Exon 17 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 659 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00659

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00355 AC: 892 AN: 251478 AF XY: 0.00350

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00567 AC: 8289 AN: 1461790 Hom.: 34 Cov.: 31 AF XY: 0.00552 AC XY: 4014 AN XY: 727194

African (AFR) AF: 0.00134 AC: 45 AN: 33476

American (AMR) AF: 0.00373 AC: 167 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

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

South Asian (SAS) AF: 0.00147 AC: 127 AN: 86256

European-Finnish (FIN) AF: 0.00249 AC: 133 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00672 AC: 7473 AN: 1111926

Other (OTH) AF: 0.00540 AC: 326 AN: 60388

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74496

African (AFR) AF: 0.00137 AC: 57 AN: 41574

American (AMR) AF: 0.00732 AC: 112 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00657 AC: 447 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00450 Hom.: 0

Bravo AF: 0.00443

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00344 AC: 418

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00539

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Cataract 18 (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.13	N
PhyloP100		4.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.052
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.0040	B
Vest4		0.34
MVP		0.38
MPC		0.17
ClinPred		0.012	T
GERP RS		3.2
Varity_R		0.020
gMVP		0.26
Mutation Taster		=96/4	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: rs41289612; hg19: chr3-45965190;