chr3-45958418-T-C

Variant names:

• chr3-45958418-T-C
• rs41289618
• NM_024513.4:c.3789A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024513.4(FYCO1):​c.3789A>G​(p.Thr1263Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,612,242 control chromosomes in the GnomAD database, including 886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (76 hom., cov: 33)
  • Exomes 𝑓: 0.032 (810 hom.)
• Consequence: FYCO1 NM_024513.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.140
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant 3-45958418-T-C is Benign according to our data. Variant chr3-45958418-T-C is described in ClinVar as Benign. ClinVar VariationId is 345501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0258 (3935/152350) while in subpopulation NFE AF = 0.0386 (2623/68028). AF 95% confidence interval is 0.0373. There are 76 homozygotes in GnomAd4. There are 1890 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	NM_024513.4	MANE Select	c.3789A>G	p.Thr1263Thr	synonymous	Exon 13 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.3789A>G	p.Thr1263Thr	synonymous	Exon 14 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.3789A>G	p.Thr1263Thr	synonymous	Exon 13 of 18	NP_001373351.1	Q9BQS8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.3789A>G	p.Thr1263Thr	synonymous	Exon 13 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.3789A>G	p.Thr1263Thr	synonymous	Exon 14 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.3789A>G	p.Thr1263Thr	synonymous	Exon 13 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3938 AN: 152232 Hom.: 76 Cov.: 33

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.0396

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0386

Gnomad OTH AF: 0.0325

GnomAD2 exomes AF: 0.0287 AC: 7143 AN: 249260 AF XY: 0.0289

Gnomad AFR exome AF: 0.00520

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0309

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0417

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0317 AC: 46206 AN: 1459892 Hom.: 810 Cov.: 32 AF XY: 0.0312 AC XY: 22693 AN XY: 726226

African (AFR) AF: 0.00464 AC: 155 AN: 33420

American (AMR) AF: 0.0253 AC: 1129 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 837 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00721 AC: 621 AN: 86134

European-Finnish (FIN) AF: 0.0421 AC: 2243 AN: 53314

Middle Eastern (MID) AF: 0.0380 AC: 170 AN: 4476

European-Non Finnish (NFE) AF: 0.0353 AC: 39293 AN: 1111826

Other (OTH) AF: 0.0292 AC: 1757 AN: 60228

GnomAD4 genome AF: 0.0258 AC: 3935 AN: 152350 Hom.: 76 Cov.: 33 AF XY: 0.0254 AC XY: 1890 AN XY: 74500

African (AFR) AF: 0.00625 AC: 260 AN: 41592

American (AMR) AF: 0.0277 AC: 424 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00579 AC: 28 AN: 4832

European-Finnish (FIN) AF: 0.0396 AC: 421 AN: 10620

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0386 AC: 2623 AN: 68028

Other (OTH) AF: 0.0317 AC: 67 AN: 2116

Alfa AF: 0.0340 Hom.: 210

Bravo AF: 0.0244

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0403

EpiControl AF: 0.0377

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 18 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.37
PhyloP100		-0.14
PromoterAI		-0.021	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs41289618; hg19: chr3-45999910;