rs149507450

Variant names:

• chr3-45967491-G-A
• rs149507450
• NM_024513.4:c.1843C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024513.4(FYCO1):​c.1843C>T​(p.Arg615Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,613,566 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. R615Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (99 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.53
• Publications: 11 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=0.004615128).
• BP6: Variant 3-45967491-G-A is Benign according to our data. Variant chr3-45967491-G-A is described in ClinVar as Benign. ClinVar VariationId is 261721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00809 (1232/152228) while in subpopulation AMR AF = 0.0122 (186/15300). AF 95% confidence interval is 0.0112. There are 9 homozygotes in GnomAd4. There are 572 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD 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.1843C>T	p.Arg615Trp	missense	Exon 8 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.1843C>T	p.Arg615Trp	missense	Exon 9 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.1843C>T	p.Arg615Trp	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.1843C>T	p.Arg615Trp	missense	Exon 8 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.1843C>T	p.Arg615Trp	missense	Exon 9 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.1843C>T	p.Arg615Trp	missense	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.00810 AC: 1232 AN: 152110 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.0107 AC: 2662 AN: 249790 AF XY: 0.00971

Gnomad AFR exome AF: 0.00177

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0106 AC: 15511 AN: 1461338 Hom.: 99 Cov.: 72 AF XY: 0.0102 AC XY: 7395 AN XY: 726982

African (AFR) AF: 0.00155 AC: 52 AN: 33478

American (AMR) AF: 0.0237 AC: 1058 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00344 AC: 90 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00351 AC: 303 AN: 86248

European-Finnish (FIN) AF: 0.0112 AC: 593 AN: 52944

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12853 AN: 1111964

Other (OTH) AF: 0.00869 AC: 525 AN: 60384

GnomAD4 genome AF: 0.00809 AC: 1232 AN: 152228 Hom.: 9 Cov.: 32 AF XY: 0.00768 AC XY: 572 AN XY: 74452

African (AFR) AF: 0.00248 AC: 103 AN: 41532

American (AMR) AF: 0.0122 AC: 186 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0119 AC: 809 AN: 67996

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00983 Hom.: 19

Bravo AF: 0.00885

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.0103 AC: 1249

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.0106

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Cataract 18 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.5
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.11
MPC		0.16
ClinPred		0.013	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.32
Mutation Taster		=99/1	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: rs149507450; hg19: chr3-46008983; COSMIC: COSV56120413;