3-45918267-T-C

Variant names:

• chr3-45918267-T-C
• rs7129
• NM_024513.4:c.*3498A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024513.4(FYCO1):​c.*3498A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 152,310 control chromosomes in the GnomAD database, including 11,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11376 hom., cov: 32)
  • Exomes 𝑓: 0.39 (15 hom.)
• Consequence: FYCO1 NM_024513.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.328
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-45918267-T-C is Benign according to our data. Variant chr3-45918267-T-C is described in ClinVar as Benign. ClinVar VariationId is 345439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

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.*3498A>G		3_prime_UTR	Exon 18 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.*3498A>G		3_prime_UTR	Exon 19 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.*3498A>G		3_prime_UTR	Exon 18 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.*3498A>G		3_prime_UTR	Exon 18 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.*3498A>G		3_prime_UTR	Exon 19 of 19	ENSP00000544318.1
	FYCO1	ENST00000965270.1		c.*3498A>G		3_prime_UTR	Exon 19 of 19	ENSP00000635329.1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55664 AN: 151954 Hom.: 11360 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.375

GnomAD4 exome AF: 0.387 AC: 92 AN: 238 Hom.: 15 Cov.: 0 AF XY: 0.390 AC XY: 57 AN XY: 146

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.389 AC: 91 AN: 234

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.366 AC: 55709 AN: 152072 Hom.: 11376 Cov.: 32 AF XY: 0.372 AC XY: 27650 AN XY: 74326

African (AFR) AF: 0.210 AC: 8706 AN: 41478

American (AMR) AF: 0.515 AC: 7861 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1346 AN: 3466

East Asian (EAS) AF: 0.650 AC: 3364 AN: 5174

South Asian (SAS) AF: 0.363 AC: 1750 AN: 4822

European-Finnish (FIN) AF: 0.435 AC: 4597 AN: 10562

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26900 AN: 67988

Other (OTH) AF: 0.380 AC: 800 AN: 2104

Alfa AF: 0.382 Hom.: 10493

Bravo AF: 0.365

Asia WGS AF: 0.517 AC: 1799 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cataract 18 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.9
DANN	Benign	0.85
PhyloP100		-0.33
Mutation Taster		=100/0	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: rs7129; hg19: chr3-45959759;