rs34068905

Variant names:

• chr3-45931176-G-A
• rs34068905
• NM_024513.4:c.4146C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024513.4(FYCO1):​c.4146C>T​(p.Ala1382Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,080 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.11
• Publications: 1 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=0.015).
• BP6: Variant 3-45931176-G-A is Benign according to our data. Variant chr3-45931176-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00833 (1269/152334) while in subpopulation AFR AF = 0.028 (1164/41564). AF 95% confidence interval is 0.0267. There are 18 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

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.4146C>T	p.Ala1382Ala	synonymous	Exon 16 of 18	NP_078789.2
	FYCO1	NM_001386421.1		c.4146C>T	p.Ala1382Ala	synonymous	Exon 17 of 19	NP_001373350.1
	FYCO1	NM_001386422.1		c.4146C>T	p.Ala1382Ala	synonymous	Exon 16 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.4146C>T	p.Ala1382Ala	synonymous	Exon 16 of 18	ENSP00000296137.2
	FYCO1	ENST00000433878.5	TSL:2	c.510C>T	p.Ala170Ala	synonymous	Exon 4 of 7	ENSP00000388136.1
	FYCO1	ENST00000438446.1	TSL:5	c.159C>T	p.Ala53Ala	synonymous	Exon 4 of 6	ENSP00000398517.1

Frequencies

GnomAD3 genomes AF: 0.00828 AC: 1260 AN: 152216 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00235 AC: 588 AN: 250628 AF XY: 0.00168

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00109 AC: 1595 AN: 1461746 Hom.: 29 Cov.: 32 AF XY: 0.000971 AC XY: 706 AN XY: 727188

African (AFR) AF: 0.0332 AC: 1112 AN: 33468

American (AMR) AF: 0.00210 AC: 94 AN: 44718

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86250

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53412

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5756

European-Non Finnish (NFE) AF: 0.000183 AC: 204 AN: 1111922

Other (OTH) AF: 0.00250 AC: 151 AN: 60386

GnomAD4 genome AF: 0.00833 AC: 1269 AN: 152334 Hom.: 18 Cov.: 33 AF XY: 0.00799 AC XY: 595 AN XY: 74494

African (AFR) AF: 0.0280 AC: 1164 AN: 41564

American (AMR) AF: 0.00392 AC: 60 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68040

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00365 Hom.: 6

Bravo AF: 0.00977

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:2

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Jun 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.2
DANN	Benign	0.56
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs34068905; hg19: chr3-45972668;