NM_024513.4:c.1206G>A

Variant names:

• chr3-45968128-C-T
• rs34147726
• NM_024513.4:c.1206G>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.1206G>A​(p.Glu402Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,614,100 control chromosomes in the GnomAD database, including 3,841 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (2053 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (1788 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.150
• Publications: 2 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=-0.62).
• BP6: Variant 3-45968128-C-T is Benign according to our data. Variant chr3-45968128-C-T is described in ClinVar as Benign. ClinVar VariationId is 261718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	NM_024513.4	MANE Select	c.1206G>A	p.Glu402Glu	synonymous	Exon 8 of 18	NP_078789.2
	FYCO1	NM_001386421.1		c.1206G>A	p.Glu402Glu	synonymous	Exon 9 of 19	NP_001373350.1
	FYCO1	NM_001386422.1		c.1206G>A	p.Glu402Glu	synonymous	Exon 8 of 18	NP_001373351.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.1206G>A	p.Glu402Glu	synonymous	Exon 8 of 18	ENSP00000296137.2
	FYCO1	ENST00000874259.1		c.1206G>A	p.Glu402Glu	synonymous	Exon 9 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.1206G>A	p.Glu402Glu	synonymous	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13428 AN: 152130 Hom.: 2052 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0223 AC: 5610 AN: 251380 AF XY: 0.0161

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00855 AC: 12493 AN: 1461852 Hom.: 1788 Cov.: 79 AF XY: 0.00728 AC XY: 5296 AN XY: 727222

African (AFR) AF: 0.314 AC: 10500 AN: 33480

American (AMR) AF: 0.0140 AC: 628 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00745 AC: 43 AN: 5768

European-Non Finnish (NFE) AF: 0.000174 AC: 193 AN: 1112010

Other (OTH) AF: 0.0181 AC: 1093 AN: 60394

GnomAD4 genome AF: 0.0883 AC: 13446 AN: 152248 Hom.: 2053 Cov.: 32 AF XY: 0.0847 AC XY: 6304 AN XY: 74464

African (AFR) AF: 0.309 AC: 12824 AN: 41486

American (AMR) AF: 0.0292 AC: 447 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68016

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0406 Hom.: 580

Bravo AF: 0.102

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.5
DANN	Benign	0.27
PhyloP100		-0.15
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: rs34147726; hg19: chr3-46009620;