3-45955269-G-A

Variant names:

• chr3-45955269-G-A
• rs1463680
• NM_024513.4:c.3924C>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.3924C>T​(p.Leu1308Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,613,656 control chromosomes in the GnomAD database, including 448,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (47608 hom., cov: 32)
  • Exomes 𝑓: 0.74 (400595 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.877
• Publications: 33 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 (REVEL=0.009).
• BP6: Variant 3-45955269-G-A is Benign according to our data. Variant chr3-45955269-G-A is described in ClinVar as Benign. ClinVar VariationId is 261734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.877 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 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.3924C>T	p.Leu1308Leu	synonymous	Exon 14 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.3924C>T	p.Leu1308Leu	synonymous	Exon 15 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.3924C>T	p.Leu1308Leu	synonymous	Exon 14 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.3924C>T	p.Leu1308Leu	synonymous	Exon 14 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000438446.1	TSL:5	c.-64C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000398517.1	C9J2W6
	FYCO1	ENST00000874259.1		c.3924C>T	p.Leu1308Leu	synonymous	Exon 15 of 19	ENSP00000544318.1

Frequencies

GnomAD3 genomes AF: 0.786 AC: 119585 AN: 152048 Hom.: 47566 Cov.: 32

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.783

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.759

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.785

GnomAD2 exomes AF: 0.792 AC: 199149 AN: 251470 AF XY: 0.788

Gnomad AFR exome AF: 0.881

Gnomad AMR exome AF: 0.861

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.960

Gnomad FIN exome AF: 0.766

Gnomad NFE exome AF: 0.721

Gnomad OTH exome AF: 0.778

GnomAD4 exome AF: 0.737 AC: 1077763 AN: 1461492 Hom.: 400595 Cov.: 54 AF XY: 0.740 AC XY: 538148 AN XY: 727052

African (AFR) AF: 0.882 AC: 29533 AN: 33476

American (AMR) AF: 0.854 AC: 38207 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 20514 AN: 26134

East Asian (EAS) AF: 0.940 AC: 37309 AN: 39700

South Asian (SAS) AF: 0.850 AC: 73306 AN: 86238

European-Finnish (FIN) AF: 0.764 AC: 40790 AN: 53410

Middle Eastern (MID) AF: 0.817 AC: 4636 AN: 5676

European-Non Finnish (NFE) AF: 0.708 AC: 786965 AN: 1111756

Other (OTH) AF: 0.770 AC: 46503 AN: 60378

GnomAD4 genome AF: 0.787 AC: 119684 AN: 152164 Hom.: 47608 Cov.: 32 AF XY: 0.790 AC XY: 58777 AN XY: 74380

African (AFR) AF: 0.876 AC: 36349 AN: 41512

American (AMR) AF: 0.818 AC: 12498 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 2716 AN: 3470

East Asian (EAS) AF: 0.958 AC: 4964 AN: 5182

South Asian (SAS) AF: 0.870 AC: 4197 AN: 4826

European-Finnish (FIN) AF: 0.759 AC: 8032 AN: 10584

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.713 AC: 48460 AN: 67996

Other (OTH) AF: 0.788 AC: 1661 AN: 2108

Alfa AF: 0.743 Hom.: 49556

Bravo AF: 0.795

Asia WGS AF: 0.916 AC: 3185 AN: 3478

EpiCase AF: 0.726

EpiControl AF: 0.724

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	-0.46
CADD	Benign	1.9
DANN	Benign	0.66
PhyloP100		-0.88
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1463680; hg19: chr3-45996761; COSMIC: COSV56114166;