rs34068905

Positions:

• chr3-45931176-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000296137.7(FYCO1):​c.4146C>T​(p.Ala1382=) 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 ENST00000296137.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.11

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-45931176-G-A is Benign according to our data. Variant chr3-45931176-G-A is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.4146C>T	p.Ala1382=	synonymous_variant	16/18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.4146C>T	p.Ala1382=	synonymous_variant	16/18	1	NM_024513.4	ENSP00000296137	P1
FYCO1	ENST00000433878.5	c.513C>T	p.Ala171=	synonymous_variant	4/7	2		ENSP00000388136
FYCO1	ENST00000438446.1	c.159C>T	p.Ala53=	synonymous_variant	4/6	5		ENSP00000398517
FYCO1	ENST00000691721.1	n.279C>T		non_coding_transcript_exon_variant	3/4

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

GnomAD3 exomes AF: 0.00235 AC: 588 AN: 250628 Hom.: 12 AF XY: 0.00168 AC XY: 228 AN XY: 135490

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 SAS exome AF: 0.000229

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

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.00250

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

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00369 Hom.: 5

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.2
DANN	Benign	0.56

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: rs34068905; hg19: chr3-45972668;