rs144182297

Variant names:

• chr3-45958428-G-C
• rs144182297
• NM_024513.4:c.3779C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-45958428-G-C
• chr3-45958428-G-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024513.4(FYCO1):​c.3779C>G​(p.Pro1260Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,612,564 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.604
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004392326).
• BP6: Variant 3-45958428-G-C is Benign according to our data. Variant chr3-45958428-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468446.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0024 (365/152338) while in subpopulation AFR AF = 0.00849 (353/41574). AF 95% confidence interval is 0.00776. There are 2 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.3779C>G	p.Pro1260Arg	missense	Exon 13 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.3779C>G	p.Pro1260Arg	missense	Exon 14 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.3779C>G	p.Pro1260Arg	missense	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.3779C>G	p.Pro1260Arg	missense	Exon 13 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.3779C>G	p.Pro1260Arg	missense	Exon 14 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.3779C>G	p.Pro1260Arg	missense	Exon 13 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152220 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00852

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000605 AC: 151 AN: 249726 AF XY: 0.000473

Gnomad AFR exome AF: 0.00842

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000205 AC: 300 AN: 1460226 Hom.: 0 Cov.: 32 AF XY: 0.000178 AC XY: 129 AN XY: 726414

African (AFR) AF: 0.00748 AC: 250 AN: 33424

American (AMR) AF: 0.000313 AC: 14 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000438 AC: 2 AN: 4562

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111948

Other (OTH) AF: 0.000448 AC: 27 AN: 60240

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152338 Hom.: 2 Cov.: 33 AF XY: 0.00243 AC XY: 181 AN XY: 74508

African (AFR) AF: 0.00849 AC: 353 AN: 41574

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000308 Hom.: 0

Bravo AF: 0.00263

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Cataract 18 (3)
-	-	1	FYCO1-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.5
DANN	Benign	0.26
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.60
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.096
Sift	Benign	0.35	T
Sift4G	Benign	0.27	T
Polyphen		0.25	B
Vest4		0.18
MVP		0.20
MPC		0.19
ClinPred		0.0044	T
GERP RS		-3.3
PromoterAI		-0.029	Neutral
Varity_R		0.020
gMVP		0.49
Mutation Taster		=300/0	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: rs144182297; hg19: chr3-45999920;