rs35678722

Variant names:

• chr3-45923752-G-A
• rs35678722
• NM_024513.4:c.4265C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-45923752-G-A
• chr3-45923752-G-C
• chr3-45923752-G-T

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.4265C>T​(p.Thr1422Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000819 in 1,613,534 control chromosomes in the GnomAD database, including 7 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (3 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.60
• 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=0.00589177).
• BP6: Variant 3-45923752-G-A is Benign according to our data. Variant chr3-45923752-G-A is described in ClinVar as Benign. ClinVar VariationId is 468449.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 = 0.00365 (556/152260) while in subpopulation AFR AF = 0.0126 (524/41538). AF 95% confidence interval is 0.0117. There are 4 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.4265C>T	p.Thr1422Met	missense	Exon 17 of 18	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.4265C>T	p.Thr1422Met	missense	Exon 18 of 19	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.4265C>T	p.Thr1422Met	missense	Exon 17 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.4265C>T	p.Thr1422Met	missense	Exon 17 of 18	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.4265C>T	p.Thr1422Met	missense	Exon 18 of 19	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.4265C>T	p.Thr1422Met	missense	Exon 17 of 18	ENSP00000635328.1

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152142 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00105 AC: 264 AN: 251460 AF XY: 0.000706

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000524 AC: 766 AN: 1461274 Hom.: 3 Cov.: 31 AF XY: 0.000448 AC XY: 326 AN XY: 727014

African (AFR) AF: 0.0128 AC: 428 AN: 33466

American (AMR) AF: 0.00125 AC: 56 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86238

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.000196 AC: 218 AN: 1111462

Other (OTH) AF: 0.000894 AC: 54 AN: 60380

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152260 Hom.: 4 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74458

African (AFR) AF: 0.0126 AC: 524 AN: 41538

American (AMR) AF: 0.000980 AC: 15 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00124 Hom.: 1

Bravo AF: 0.00415

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00116 AC: 141

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.81	N
PhyloP100		2.6
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.025
Sift	Benign	0.23	T
Sift4G	Benign	0.32	T
Polyphen		0.20	B
Vest4		0.30
MVP		0.30
MPC		0.18
ClinPred		0.0054	T
GERP RS		2.2
Varity_R		0.015
gMVP		0.21
Mutation Taster		=96/4	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: rs35678722; hg19: chr3-45965244; COSMIC: COSV56116344;