3-45918023-A-T

Variant names:

• chr3-45918023-A-T
• rs7130
• NM_024513.4:c.*3742T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024513.4(FYCO1):​c.*3742T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 152,702 control chromosomes in the GnomAD database, including 53,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53619 hom., cov: 32)
  • Exomes 𝑓: 0.81 (137 hom.)
• Consequence: FYCO1 NM_024513.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.402

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-45918023-A-T is Benign according to our data. Variant chr3-45918023-A-T is described in ClinVar as [Benign]. Clinvar id is 345435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.*3742T>A		3_prime_UTR_variant	Exon 18 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137	c.*3742T>A		3_prime_UTR_variant	Exon 18 of 18	1	NM_024513.4	ENSP00000296137.2
FYCO1	ENST00000433878	c.*3395T>A		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000388136.1

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126977 AN: 152148 Hom.: 53561 Cov.: 32

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.888

Gnomad ASJ AF: 0.846

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.846

GnomAD4 exome AF: 0.807 AC: 352 AN: 436 Hom.: 137 Cov.: 0 AF XY: 0.807 AC XY: 213 AN XY: 264

Gnomad4 FIN exome AF: 0.805

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.835 AC: 127094 AN: 152266 Hom.: 53619 Cov.: 32 AF XY: 0.838 AC XY: 62413 AN XY: 74442

Gnomad4 AFR AF: 0.927

Gnomad4 AMR AF: 0.888

Gnomad4 ASJ AF: 0.846

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.919

Gnomad4 FIN AF: 0.780

Gnomad4 NFE AF: 0.758

Gnomad4 OTH AF: 0.849

Alfa AF: 0.797 Hom.: 6034

Bravo AF: 0.847

Asia WGS AF: 0.964 AC: 3350 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.3
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs7130; hg19: chr3-45959515;