chr3-45936374-C-T

Variant names:

• chr3-45936374-C-T
• rs4535265
• NM_024513.4:c.4040+74G>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.4040+74G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 975,800 control chromosomes in the GnomAD database, including 81,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10653 hom., cov: 32)
  • Exomes 𝑓: 0.41 (70830 hom.)
• Consequence: FYCO1 NM_024513.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.284
• Publications: 8 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 (BayesDel_noAF=-0.83).
• BP6: Variant 3-45936374-C-T is Benign according to our data. Variant chr3-45936374-C-T is described in ClinVar as Benign. ClinVar VariationId is 1257804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.4040+74G>A		intron_variant	Intron 15 of 17	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.4040+74G>A		intron_variant	Intron 15 of 17	1	NM_024513.4	ENSP00000296137.2
FYCO1	ENST00000433878.5	c.404+74G>A		intron_variant	Intron 3 of 6	2		ENSP00000388136.1
FYCO1	ENST00000438446.1	c.53+74G>A		intron_variant	Intron 3 of 5	5		ENSP00000398517.1
FYCO1	ENST00000691721.1	n.173+74G>A		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51933 AN: 151988 Hom.: 10639 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.357

GnomAD4 exome AF: 0.405 AC: 333963 AN: 823694 Hom.: 70830 AF XY: 0.400 AC XY: 174420 AN XY: 435544

African (AFR) AF: 0.127 AC: 2713 AN: 21334

American (AMR) AF: 0.586 AC: 25653 AN: 43812

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 8475 AN: 22098

East Asian (EAS) AF: 0.611 AC: 22429 AN: 36724

South Asian (SAS) AF: 0.352 AC: 25842 AN: 73492

European-Finnish (FIN) AF: 0.432 AC: 21960 AN: 50880

Middle Eastern (MID) AF: 0.344 AC: 1346 AN: 3912

European-Non Finnish (NFE) AF: 0.394 AC: 209661 AN: 532152

Other (OTH) AF: 0.404 AC: 15884 AN: 39290

GnomAD4 genome AF: 0.342 AC: 51969 AN: 152106 Hom.: 10653 Cov.: 32 AF XY: 0.349 AC XY: 25934 AN XY: 74332

African (AFR) AF: 0.132 AC: 5466 AN: 41532

American (AMR) AF: 0.502 AC: 7675 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1336 AN: 3468

East Asian (EAS) AF: 0.657 AC: 3392 AN: 5162

South Asian (SAS) AF: 0.361 AC: 1738 AN: 4818

European-Finnish (FIN) AF: 0.439 AC: 4643 AN: 10572

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26547 AN: 67962

Other (OTH) AF: 0.362 AC: 763 AN: 2106

Alfa AF: 0.347 Hom.: 4560

Bravo AF: 0.337

Asia WGS AF: 0.508 AC: 1765 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.77
PhyloP100		0.28
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: rs4535265; hg19: chr3-45977866;