rs13071283

Variant names:

• chr3-45968515-T-C
• rs13071283
• NM_024513.4:c.819A>G

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.819A>G​(p.Gln273Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,932 control chromosomes in the GnomAD database, including 14,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (1030 hom., cov: 33)
  • Exomes 𝑓: 0.12 (13016 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.535
• Publications: 15 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=-0.85).
• BP6: Variant 3-45968515-T-C is Benign according to our data. Variant chr3-45968515-T-C is described in ClinVar as Benign. ClinVar VariationId is 261737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.535 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.328 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.819A>G	p.Gln273Gln	synonymous	Exon 8 of 18	NP_078789.2
	FYCO1	NM_001386421.1		c.819A>G	p.Gln273Gln	synonymous	Exon 9 of 19	NP_001373350.1
	FYCO1	NM_001386422.1		c.819A>G	p.Gln273Gln	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.819A>G	p.Gln273Gln	synonymous	Exon 8 of 18	ENSP00000296137.2

Frequencies

GnomAD3 genomes AF: 0.0936 AC: 14247 AN: 152148 Hom.: 1031 Cov.: 33

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.0694

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0986

GnomAD2 exomes AF: 0.127 AC: 31921 AN: 251290 AF XY: 0.142

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.0647

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.117 AC: 170480 AN: 1461666 Hom.: 13016 Cov.: 85 AF XY: 0.125 AC XY: 90809 AN XY: 727150

African (AFR) AF: 0.0295 AC: 986 AN: 33480

American (AMR) AF: 0.0669 AC: 2991 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5096 AN: 26136

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39700

South Asian (SAS) AF: 0.335 AC: 28894 AN: 86258

European-Finnish (FIN) AF: 0.144 AC: 7651 AN: 53216

Middle Eastern (MID) AF: 0.198 AC: 1142 AN: 5768

European-Non Finnish (NFE) AF: 0.105 AC: 116326 AN: 1111994

Other (OTH) AF: 0.121 AC: 7312 AN: 60390

GnomAD4 genome AF: 0.0935 AC: 14243 AN: 152266 Hom.: 1030 Cov.: 33 AF XY: 0.0991 AC XY: 7382 AN XY: 74454

African (AFR) AF: 0.0305 AC: 1267 AN: 41570

American (AMR) AF: 0.0692 AC: 1059 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 681 AN: 3468

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5180

South Asian (SAS) AF: 0.342 AC: 1648 AN: 4816

European-Finnish (FIN) AF: 0.145 AC: 1539 AN: 10608

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7558 AN: 68010

Other (OTH) AF: 0.0994 AC: 210 AN: 2112

Alfa AF: 0.105 Hom.: 758

Bravo AF: 0.0775

Asia WGS AF: 0.172 AC: 599 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.115

ClinVar

ClinVar submissions as Germline

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	-0.85
CADD	Benign	2.9
DANN	Benign	0.23
PhyloP100		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs13071283; hg19: chr3-46010007; COSMIC: COSV56113537;