rs34266136

Variant names:

• chr3-45967040-C-T
• rs34266136
• NM_024513.4:c.2294G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024513.4(FYCO1):​c.2294G>A​(p.Arg765His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,613,492 control chromosomes in the GnomAD database, including 47 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (26 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00
• Publications: 5 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=0.0026426911).
• BP6: Variant 3-45967040-C-T is Benign according to our data. Variant chr3-45967040-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00777 (1183/152342) while in subpopulation AFR AF = 0.0266 (1105/41582). AF 95% confidence interval is 0.0253. There are 21 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.2294G>A	p.Arg765His	missense	Exon 8 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.2294G>A	p.Arg765His	missense	Exon 9 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.2294G>A	p.Arg765His	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.2294G>A	p.Arg765His	missense	Exon 8 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.2294G>A	p.Arg765His	missense	Exon 9 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.2294G>A	p.Arg765His	missense	Exon 8 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1179 AN: 152224 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00215 AC: 538 AN: 250600 AF XY: 0.00158

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000924 AC: 1350 AN: 1461150 Hom.: 26 Cov.: 37 AF XY: 0.000795 AC XY: 578 AN XY: 726880

African (AFR) AF: 0.0312 AC: 1045 AN: 33478

American (AMR) AF: 0.00192 AC: 86 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86256

European-Finnish (FIN) AF: 0.0000569 AC: 3 AN: 52700

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.0000612 AC: 68 AN: 1112004

Other (OTH) AF: 0.00187 AC: 113 AN: 60386

GnomAD4 genome AF: 0.00777 AC: 1183 AN: 152342 Hom.: 21 Cov.: 33 AF XY: 0.00742 AC XY: 553 AN XY: 74494

African (AFR) AF: 0.0266 AC: 1105 AN: 41582

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68034

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00298 Hom.: 13

Bravo AF: 0.00921

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0256 AC: 113

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00253 AC: 307

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 18 (2)
-	-	2	not provided (2)
-	-	1	FYCO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.043
DANN	Benign	0.79
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.41	N
PhyloP100		0.0
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.027
Sift	Benign	0.14	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.050
MVP		0.081
MPC		0.20
ClinPred		0.011	T
GERP RS		-9.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.058
Mutation Taster		=100/0	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: rs34266136; hg19: chr3-46008532;