chr3-45979726-G-T

Variant names:

• chr3-45979726-G-T
• rs4682801
• NM_024513.4:c.267C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024513.4(FYCO1):​c.267C>A​(p.Arg89Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 1,613,298 control chromosomes in the GnomAD database, including 484,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (39463 hom., cov: 33)
  • Exomes 𝑓: 0.78 (445142 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.344
• Publications: 30 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-45979726-G-T is Benign according to our data. Variant chr3-45979726-G-T is described in ClinVar as Benign. ClinVar VariationId is 261723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.344 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.267C>A	p.Arg89Arg	synonymous	Exon 4 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.267C>A	p.Arg89Arg	synonymous	Exon 5 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.267C>A	p.Arg89Arg	synonymous	Exon 4 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.267C>A	p.Arg89Arg	synonymous	Exon 4 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.267C>A	p.Arg89Arg	synonymous	Exon 5 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.267C>A	p.Arg89Arg	synonymous	Exon 4 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106144 AN: 152014 Hom.: 39435 Cov.: 33

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.841

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.751

GnomAD2 exomes AF: 0.808 AC: 203219 AN: 251496 AF XY: 0.815

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 0.846

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.810

Gnomad NFE exome AF: 0.774

Gnomad OTH exome AF: 0.814

GnomAD4 exome AF: 0.776 AC: 1134220 AN: 1461166 Hom.: 445142 Cov.: 50 AF XY: 0.781 AC XY: 568002 AN XY: 726918

African (AFR) AF: 0.423 AC: 14168 AN: 33464

American (AMR) AF: 0.892 AC: 39903 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 22085 AN: 26122

East Asian (EAS) AF: 0.999 AC: 39669 AN: 39690

South Asian (SAS) AF: 0.899 AC: 77580 AN: 86252

European-Finnish (FIN) AF: 0.806 AC: 43002 AN: 53364

Middle Eastern (MID) AF: 0.882 AC: 5084 AN: 5766

European-Non Finnish (NFE) AF: 0.760 AC: 845029 AN: 1111442

Other (OTH) AF: 0.790 AC: 47700 AN: 60346

GnomAD4 genome AF: 0.698 AC: 106218 AN: 152132 Hom.: 39463 Cov.: 33 AF XY: 0.708 AC XY: 52671 AN XY: 74368

African (AFR) AF: 0.430 AC: 17798 AN: 41438

American (AMR) AF: 0.841 AC: 12861 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2918 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5170 AN: 5174

South Asian (SAS) AF: 0.909 AC: 4391 AN: 4832

European-Finnish (FIN) AF: 0.809 AC: 8569 AN: 10598

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.766 AC: 52065 AN: 68006

Other (OTH) AF: 0.754 AC: 1593 AN: 2112

Alfa AF: 0.749 Hom.: 68764

Bravo AF: 0.687

Asia WGS AF: 0.939 AC: 3262 AN: 3478

EpiCase AF: 0.781

EpiControl AF: 0.781

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
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.99
DANN	Benign	0.72
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	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: rs4682801; hg19: chr3-46021218; COSMIC: COSV108101686; COSMIC: COSV108101686;