3-45966595-G-A

Variant names:

• chr3-45966595-G-A
• rs13079869
• NM_024513.4:c.2739C>T

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.2739C>T​(p.Cys913Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,126 control chromosomes in the GnomAD database, including 13,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (993 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12770 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.421
• Publications: 17 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=-0.87).
• BP6: Variant 3-45966595-G-A is Benign according to our data. Variant chr3-45966595-G-A is described in ClinVar as Benign. ClinVar VariationId is 261724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.421 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	NM_024513.4	MANE Select	c.2739C>T	p.Cys913Cys	synonymous	Exon 8 of 18	NP_078789.2
	FYCO1	NM_001386421.1		c.2739C>T	p.Cys913Cys	synonymous	Exon 9 of 19	NP_001373350.1
	FYCO1	NM_001386422.1		c.2739C>T	p.Cys913Cys	synonymous	Exon 8 of 18	NP_001373351.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.2739C>T	p.Cys913Cys	synonymous	Exon 8 of 18	ENSP00000296137.2
	FYCO1	ENST00000874259.1		c.2739C>T	p.Cys913Cys	synonymous	Exon 9 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.2739C>T	p.Cys913Cys	synonymous	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.0892 AC: 13575 AN: 152198 Hom.: 994 Cov.: 33

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.0646

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0904

GnomAD2 exomes AF: 0.125 AC: 31213 AN: 250258 AF XY: 0.140

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.0612

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.115 AC: 168290 AN: 1461810 Hom.: 12770 Cov.: 39 AF XY: 0.123 AC XY: 89745 AN XY: 727198

African (AFR) AF: 0.0179 AC: 598 AN: 33480

American (AMR) AF: 0.0631 AC: 2822 AN: 44722

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

East Asian (EAS) AF: 0.00204 AC: 81 AN: 39700

South Asian (SAS) AF: 0.334 AC: 28849 AN: 86256

European-Finnish (FIN) AF: 0.144 AC: 7689 AN: 53344

Middle Eastern (MID) AF: 0.189 AC: 1089 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115361 AN: 1112008

Other (OTH) AF: 0.117 AC: 7091 AN: 60396

GnomAD4 genome AF: 0.0891 AC: 13570 AN: 152316 Hom.: 993 Cov.: 33 AF XY: 0.0950 AC XY: 7076 AN XY: 74476

African (AFR) AF: 0.0197 AC: 820 AN: 41590

American (AMR) AF: 0.0645 AC: 986 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 629 AN: 3464

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5186

South Asian (SAS) AF: 0.341 AC: 1647 AN: 4826

European-Finnish (FIN) AF: 0.145 AC: 1542 AN: 10616

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

European-Non Finnish (NFE) AF: 0.110 AC: 7474 AN: 68020

Other (OTH) AF: 0.0914 AC: 193 AN: 2112

Alfa AF: 0.102 Hom.: 1544

Bravo AF: 0.0723

Asia WGS AF: 0.170 AC: 591 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.113

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	-0.87
CADD	Benign	0.68
DANN	Benign	0.31
PhyloP100		-0.42
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)		0.010		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: rs13079869; hg19: chr3-46008087; COSMIC: COSV56118246;