NM_024513.4:c.3003C>A

Variant names:

• chr3-45966331-G-T
• rs13079478
• NM_024513.4:c.3003C>A

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.3003C>A​(p.Asn1001Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,960 control chromosomes in the GnomAD database, including 13,741 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. N1001E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.088 (971 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12770 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.322
• Publications: 32 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=0.0032511652).
• BP6: Variant 3-45966331-G-T is Benign according to our data. Variant chr3-45966331-G-T is described in ClinVar as Benign. ClinVar VariationId is 261729.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	NM_024513.4	MANE Select	c.3003C>A	p.Asn1001Lys	missense	Exon 8 of 18	NP_078789.2
	FYCO1	NM_001386421.1		c.3003C>A	p.Asn1001Lys	missense	Exon 9 of 19	NP_001373350.1
	FYCO1	NM_001386422.1		c.3003C>A	p.Asn1001Lys	missense	Exon 8 of 18	NP_001373351.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	ENST00000296137.7	TSL:1 MANE Select	c.3003C>A	p.Asn1001Lys	missense	Exon 8 of 18	ENSP00000296137.2

Frequencies

GnomAD3 genomes AF: 0.0885 AC: 13468 AN: 152166 Hom.: 972 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0908

GnomAD2 exomes AF: 0.124 AC: 31070 AN: 249724 AF XY: 0.139

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.0609

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.00266

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.115 AC: 168149 AN: 1461676 Hom.: 12770 Cov.: 37 AF XY: 0.123 AC XY: 89680 AN XY: 727152

African (AFR) AF: 0.0159 AC: 532 AN: 33476

American (AMR) AF: 0.0628 AC: 2807 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4707 AN: 26126

East Asian (EAS) AF: 0.00204 AC: 81 AN: 39700

South Asian (SAS) AF: 0.335 AC: 28879 AN: 86250

European-Finnish (FIN) AF: 0.144 AC: 7682 AN: 53372

Middle Eastern (MID) AF: 0.189 AC: 1089 AN: 5764

European-Non Finnish (NFE) AF: 0.104 AC: 115293 AN: 1111876

Other (OTH) AF: 0.117 AC: 7079 AN: 60390

GnomAD4 genome AF: 0.0884 AC: 13461 AN: 152284 Hom.: 971 Cov.: 33 AF XY: 0.0944 AC XY: 7029 AN XY: 74464

African (AFR) AF: 0.0178 AC: 741 AN: 41574

American (AMR) AF: 0.0642 AC: 983 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 627 AN: 3466

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5186

South Asian (SAS) AF: 0.342 AC: 1651 AN: 4830

European-Finnish (FIN) AF: 0.144 AC: 1531 AN: 10602

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7457 AN: 68002

Other (OTH) AF: 0.0918 AC: 194 AN: 2114

Alfa AF: 0.0992 Hom.: 1554

Bravo AF: 0.0716

TwinsUK AF: 0.0992 AC: 368

ALSPAC AF: 0.0986 AC: 380

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.126 AC: 15337

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.113

ClinVar

ClinVar submissions as Germline

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	Uncertain	0.34
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.32
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.11
Sift	Benign	0.098	T
Sift4G	Benign	0.19	T
Polyphen		0.0080	B
Vest4		0.025
MutPred		0.25		Gain of ubiquitination at N1001 (P = 0.0022)
MPC		0.19
ClinPred		0.00044	T
GERP RS		1.4
Varity_R		0.066
gMVP		0.067
Mutation Taster		=99/1	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: rs13079478; hg19: chr3-46007823;