chr3-45966333-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024513.4(FYCO1):​c.3001A>C​(p.Asn1001His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1001D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.912

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08151275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FYCO1	NM_024513.4	c.3001A>C	p.Asn1001His	missense_variant	Exon 8 of 18	ENST00000296137.7	NP_078789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FYCO1	ENST00000296137.7	c.3001A>C	p.Asn1001His	missense_variant	Exon 8 of 18	1	NM_024513.4	ENSP00000296137.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0023	.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.075
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		0.24	.;B
Vest4		0.10
MutPred		0.17		Gain of catalytic residue at L1003 (P = 0.0727);Gain of catalytic residue at L1003 (P = 0.0727);
MVP		0.71
MPC		0.25
ClinPred		0.19	T
GERP RS		2.3
Varity_R		0.052
gMVP		0.087

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-46007825;