chr3-45967995-G-A

Variant names:

• chr3-45967995-G-A
• rs33910087
• NM_024513.4:c.1339C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024513.4(FYCO1):​c.1339C>T​(p.Arg447Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,916 control chromosomes in the GnomAD database, including 13,793 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R447H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.092 (1004 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12789 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.816
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002291739).
• BP6: Variant 3-45967995-G-A is Benign according to our data. Variant chr3-45967995-G-A is described in ClinVar as Benign. ClinVar VariationId is 261720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.327 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	NM_024513.4	MANE Select	c.1339C>T	p.Arg447Cys	missense	Exon 8 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.1339C>T	p.Arg447Cys	missense	Exon 9 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.1339C>T	p.Arg447Cys	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.1339C>T	p.Arg447Cys	missense	Exon 8 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.1339C>T	p.Arg447Cys	missense	Exon 9 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.1339C>T	p.Arg447Cys	missense	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14006 AN: 151952 Hom.: 1005 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00367

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0943

GnomAD2 exomes AF: 0.125 AC: 31541 AN: 251438 AF XY: 0.140

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.0613

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.115 AC: 168692 AN: 1461846 Hom.: 12789 Cov.: 75 AF XY: 0.124 AC XY: 89921 AN XY: 727224

African (AFR) AF: 0.0277 AC: 927 AN: 33480

American (AMR) AF: 0.0633 AC: 2832 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4710 AN: 26136

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39698

South Asian (SAS) AF: 0.335 AC: 28876 AN: 86258

European-Finnish (FIN) AF: 0.144 AC: 7697 AN: 53402

Middle Eastern (MID) AF: 0.189 AC: 1091 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115348 AN: 1111984

Other (OTH) AF: 0.118 AC: 7129 AN: 60396

GnomAD4 genome AF: 0.0921 AC: 13999 AN: 152070 Hom.: 1004 Cov.: 32 AF XY: 0.0979 AC XY: 7280 AN XY: 74340

African (AFR) AF: 0.0298 AC: 1238 AN: 41490

American (AMR) AF: 0.0664 AC: 1015 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 629 AN: 3468

East Asian (EAS) AF: 0.00368 AC: 19 AN: 5168

South Asian (SAS) AF: 0.340 AC: 1636 AN: 4806

European-Finnish (FIN) AF: 0.145 AC: 1533 AN: 10562

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7470 AN: 67968

Other (OTH) AF: 0.0953 AC: 201 AN: 2110

Alfa AF: 0.101 Hom.: 2210

Bravo AF: 0.0756

TwinsUK AF: 0.102 AC: 378

ALSPAC AF: 0.101 AC: 390

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.110 AC: 948

ExAC AF: 0.128 AC: 15483

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cataract 18 (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.6
DANN	Benign	0.92
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.82
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.059
Sift	Benign	0.048	D
Sift4G	Uncertain	0.037	D
Polyphen		0.95	P
Vest4		0.051
MPC		0.22
ClinPred		0.0036	T
GERP RS		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.079
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: rs33910087; hg19: chr3-46009487; COSMIC: COSV56115935;