rs387906964

Variant names:

• chr3-45967128-G-A
• rs387906964
• NM_024513.4:c.2206C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_024513.4(FYCO1):​c.2206C>T​(p.Gln736*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FYCO1 NM_024513.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.05
• Publications: 9 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-45967128-G-A is Pathogenic according to our data. Variant chr3-45967128-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30646.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2206C>T	p.Gln736*	stop_gained	Exon 8 of 18	NP_078789.2
	FYCO1	NM_001386421.1		c.2206C>T	p.Gln736*	stop_gained	Exon 9 of 19	NP_001373350.1
	FYCO1	NM_001386422.1		c.2206C>T	p.Gln736*	stop_gained	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.2206C>T	p.Gln736*	stop_gained	Exon 8 of 18	ENSP00000296137.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251164 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461588 Hom.: 0 Cov.: 37 AF XY: 0.00000688 AC XY: 5 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cataract 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.66	D
PhyloP100		1.0
Vest4		0.075
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs387906964; hg19: chr3-46008620;