rs3796376

Variant names:

• chr3-45967999-C-T
• rs3796376
• NM_024513.4:c.1335G>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.1335G>A​(p.Leu445Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,614,032 control chromosomes in the GnomAD database, including 30,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2226 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27909 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.103
• Publications: 22 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 3-45967999-C-T is Benign according to our data. Variant chr3-45967999-C-T is described in ClinVar as Benign. ClinVar VariationId is 261719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 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.1335G>A	p.Leu445Leu	synonymous	Exon 8 of 18	NP_078789.2
	FYCO1	NM_001386421.1		c.1335G>A	p.Leu445Leu	synonymous	Exon 9 of 19	NP_001373350.1
	FYCO1	NM_001386422.1		c.1335G>A	p.Leu445Leu	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.1335G>A	p.Leu445Leu	synonymous	Exon 8 of 18	ENSP00000296137.2

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23996 AN: 152042 Hom.: 2223 Cov.: 32

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.183 AC: 46021 AN: 251450 AF XY: 0.186

Gnomad AFR exome AF: 0.0604

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.285

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.206

GnomAD4 exome AF: 0.191 AC: 279749 AN: 1461872 Hom.: 27909 Cov.: 81 AF XY: 0.191 AC XY: 139213 AN XY: 727236

African (AFR) AF: 0.0586 AC: 1963 AN: 33480

American (AMR) AF: 0.146 AC: 6545 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 5426 AN: 26136

East Asian (EAS) AF: 0.298 AC: 11832 AN: 39700

South Asian (SAS) AF: 0.155 AC: 13361 AN: 86258

European-Finnish (FIN) AF: 0.180 AC: 9598 AN: 53408

Middle Eastern (MID) AF: 0.239 AC: 1379 AN: 5768

European-Non Finnish (NFE) AF: 0.196 AC: 218066 AN: 1112002

Other (OTH) AF: 0.192 AC: 11579 AN: 60396

GnomAD4 genome AF: 0.158 AC: 23997 AN: 152160 Hom.: 2226 Cov.: 32 AF XY: 0.157 AC XY: 11674 AN XY: 74374

African (AFR) AF: 0.0641 AC: 2661 AN: 41542

American (AMR) AF: 0.170 AC: 2601 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 707 AN: 3470

East Asian (EAS) AF: 0.279 AC: 1441 AN: 5156

South Asian (SAS) AF: 0.154 AC: 741 AN: 4822

European-Finnish (FIN) AF: 0.168 AC: 1778 AN: 10592

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.199 AC: 13548 AN: 67960

Other (OTH) AF: 0.190 AC: 402 AN: 2116

Alfa AF: 0.178 Hom.: 1277

Bravo AF: 0.159

Asia WGS AF: 0.189 AC: 655 AN: 3478

EpiCase AF: 0.208

EpiControl AF: 0.202

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	0.58
DANN	Benign	0.49
PhyloP100		0.10
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: rs3796376; hg19: chr3-46009491; COSMIC: COSV56113661;