rs13059238

Variant names:

• chr3-45966333-T-C
• rs13059238
• NM_024513.4:c.3001A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-45966333-T-C
• chr3-45966333-T-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.3001A>G​(p.Asn1001Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,892 control chromosomes in the GnomAD database, including 14,017 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. N1001E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.093 (1007 hom., cov: 33)
  • Exomes 𝑓: 0.12 (13010 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.912
• Publications: 29 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=0.0027463734).
• BP6: Variant 3-45966333-T-C is Benign according to our data. Variant chr3-45966333-T-C is described in ClinVar as Benign. ClinVar VariationId is 261728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.328 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.3001A>G	p.Asn1001Asp	missense	Exon 8 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.3001A>G	p.Asn1001Asp	missense	Exon 9 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.3001A>G	p.Asn1001Asp	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.3001A>G	p.Asn1001Asp	missense	Exon 8 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.3001A>G	p.Asn1001Asp	missense	Exon 9 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.3001A>G	p.Asn1001Asp	missense	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.0934 AC: 14209 AN: 152086 Hom.: 1008 Cov.: 33

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.0693

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.00367

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0981

GnomAD2 exomes AF: 0.127 AC: 31697 AN: 249768 AF XY: 0.142

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.0647

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.00266

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.117 AC: 170442 AN: 1461688 Hom.: 13010 Cov.: 37 AF XY: 0.125 AC XY: 90798 AN XY: 727162

African (AFR) AF: 0.0294 AC: 985 AN: 33478

American (AMR) AF: 0.0669 AC: 2990 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5093 AN: 26126

East Asian (EAS) AF: 0.00204 AC: 81 AN: 39698

South Asian (SAS) AF: 0.335 AC: 28891 AN: 86248

European-Finnish (FIN) AF: 0.144 AC: 7685 AN: 53386

Middle Eastern (MID) AF: 0.198 AC: 1140 AN: 5764

European-Non Finnish (NFE) AF: 0.105 AC: 116269 AN: 1111878

Other (OTH) AF: 0.121 AC: 7308 AN: 60390

GnomAD4 genome AF: 0.0933 AC: 14205 AN: 152204 Hom.: 1007 Cov.: 33 AF XY: 0.0989 AC XY: 7360 AN XY: 74420

African (AFR) AF: 0.0305 AC: 1268 AN: 41548

American (AMR) AF: 0.0691 AC: 1058 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 678 AN: 3468

East Asian (EAS) AF: 0.00368 AC: 19 AN: 5166

South Asian (SAS) AF: 0.342 AC: 1650 AN: 4828

European-Finnish (FIN) AF: 0.144 AC: 1533 AN: 10610

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7529 AN: 67964

Other (OTH) AF: 0.0990 AC: 209 AN: 2112

Alfa AF: 0.0877 Hom.: 451

Bravo AF: 0.0775

TwinsUK AF: 0.100 AC: 371

ALSPAC AF: 0.0996 AC: 384

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.129 AC: 15646

Asia WGS AF: 0.172 AC: 599 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.115

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	0.062
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.42
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.91
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.18
ClinPred		0.00036	T
GERP RS		2.3
Varity_R		0.046
gMVP		0.060
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: rs13059238; hg19: chr3-46007825;