rs1463680

chr3-45955269-G-Achr3-45955269-G-Cchr3-45955269-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024513.4(FYCO1):c.3924C>T(p.Leu1308=) 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:5
• Conservation: PhyloP100: -0.877

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 3-45955269-G-A is Benign according to our data. Variant chr3-45955269-G-A is described in ClinVar as [Benign]. Clinvar id is 261734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45955269-G-A is described in Lovd as [Benign]. Variant chr3-45955269-G-A is described in Lovd as [Likely_benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.3924C>T	p.Leu1308=	synonymous_variant	14/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.3924C>T	p.Leu1308=	synonymous_variant	14/18	1	NM_024513.4	P1
FYCO1	ENST00000433878.5	c.291C>T	p.Leu97=	synonymous_variant	2/7	2
FYCO1	ENST00000438446.1	c.-64C>T		5_prime_UTR_variant	2/6	5

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

GnomAD3 exomes AF: 0.792 AC: 199149 AN: 251470 Hom.: 79740 AF XY: 0.788 AC XY: 107079 AN XY: 135906

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 SAS exome AF: 0.851

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

Gnomad4 AFR exome AF: 0.882

Gnomad4 AMR exome AF: 0.854

Gnomad4 ASJ exome AF: 0.785

Gnomad4 EAS exome AF: 0.940

Gnomad4 SAS exome AF: 0.850

Gnomad4 FIN exome AF: 0.764

Gnomad4 NFE exome AF: 0.708

Gnomad4 OTH exome AF: 0.770

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

Gnomad4 AFR AF: 0.876

Gnomad4 AMR AF: 0.818

Gnomad4 ASJ AF: 0.783

Gnomad4 EAS AF: 0.958

Gnomad4 SAS AF: 0.870

Gnomad4 FIN AF: 0.759

Gnomad4 NFE AF: 0.713

Gnomad4 OTH AF: 0.788

Alfa AF: 0.743 Hom.: 44216

Bravo AF: 0.795

Asia WGS AF: 0.916 AC: 3185 AN: 3478

EpiCase AF: 0.726

EpiControl AF: 0.724

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	1.9
Dann	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs1463680; hg19: chr3-45996761; COSMIC: COSV56114166;