3-45968372-C-G

Variant names:

• chr3-45968372-C-G
• rs3733100
• NM_024513.4:c.962G>C

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.962G>C​(p.Gly321Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 1,613,190 control chromosomes in the GnomAD database, including 242,056 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G321C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.48 (19302 hom., cov: 32)
  • Exomes 𝑓: 0.55 (222754 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.49
• Publications: 42 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 (MetaRNN=2.394217E-6).
• BP6: Variant 3-45968372-C-G is Benign according to our data. Variant chr3-45968372-C-G is described in ClinVar as Benign. ClinVar VariationId is 261738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.689 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.962G>C	p.Gly321Ala	missense	Exon 8 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.962G>C	p.Gly321Ala	missense	Exon 9 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.962G>C	p.Gly321Ala	missense	Exon 8 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.962G>C	p.Gly321Ala	missense	Exon 8 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.962G>C	p.Gly321Ala	missense	Exon 9 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.962G>C	p.Gly321Ala	missense	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72518 AN: 151916 Hom.: 19287 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.490

GnomAD2 exomes AF: 0.577 AC: 144817 AN: 250930 AF XY: 0.583

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.676

Gnomad FIN exome AF: 0.622

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.547 AC: 799313 AN: 1461156 Hom.: 222754 Cov.: 71 AF XY: 0.552 AC XY: 401240 AN XY: 726878

African (AFR) AF: 0.228 AC: 7626 AN: 33480

American (AMR) AF: 0.668 AC: 29880 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 15343 AN: 26136

East Asian (EAS) AF: 0.643 AC: 25520 AN: 39696

South Asian (SAS) AF: 0.695 AC: 59926 AN: 86256

European-Finnish (FIN) AF: 0.607 AC: 32080 AN: 52848

Middle Eastern (MID) AF: 0.555 AC: 3204 AN: 5768

European-Non Finnish (NFE) AF: 0.533 AC: 592178 AN: 1111864

Other (OTH) AF: 0.556 AC: 33556 AN: 60388

GnomAD4 genome AF: 0.477 AC: 72557 AN: 152034 Hom.: 19302 Cov.: 32 AF XY: 0.489 AC XY: 36299 AN XY: 74290

African (AFR) AF: 0.239 AC: 9900 AN: 41474

American (AMR) AF: 0.600 AC: 9173 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2030 AN: 3464

East Asian (EAS) AF: 0.680 AC: 3504 AN: 5152

South Asian (SAS) AF: 0.709 AC: 3417 AN: 4818

European-Finnish (FIN) AF: 0.621 AC: 6557 AN: 10562

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36241 AN: 67960

Other (OTH) AF: 0.497 AC: 1048 AN: 2110

Alfa AF: 0.524 Hom.: 13650

Bravo AF: 0.459

TwinsUK AF: 0.536 AC: 1987

ALSPAC AF: 0.542 AC: 2089

ESP6500AA AF: 0.246 AC: 1086

ESP6500EA AF: 0.544 AC: 4678

ExAC AF: 0.567 AC: 68779

Asia WGS AF: 0.693 AC: 2410 AN: 3478

EpiCase AF: 0.539

EpiControl AF: 0.543

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cataract 18 (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.074
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0000024	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N
PhyloP100		2.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.073
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.17
ClinPred		0.00091	T
GERP RS		3.8
Varity_R		0.022
gMVP		0.046
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: rs3733100; hg19: chr3-46009864; COSMIC: COSV56114194;