rs71622515

Variant names:

• chr3-45966331-GTT-TTC
• rs71622515
• NM_024513.4:c.3001_3003delAACinsGAA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_024513.4(FYCO1):​c.3001_3003delAACinsGAA​(p.Asn1001Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.12 in 33,601 alleles, including 3,175 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1001K) has been classified as Benign.

• Frequency: GnomAD MNV: 𝑓 0.12 Genomes: not found (cov: 33)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.96
• Publications: 4 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 -9 ACMG points.

• BP6: Variant 3-45966331-GTT-TTC is Benign according to our data. Variant chr3-45966331-GTT-TTC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261727.
• BA1: GnomAdMnv highest population allele frequency = 0.12 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYCO1	NM_024513.4	MANE Select	c.3001_3003delAACinsGAA	p.Asn1001Glu	missense	N/A	NP_078789.2	Q9BQS8-1
	FYCO1	NM_001386421.1		c.3001_3003delAACinsGAA	p.Asn1001Glu	missense	N/A	NP_001373350.1	Q9BQS8-1
	FYCO1	NM_001386422.1		c.3001_3003delAACinsGAA	p.Asn1001Glu	missense	N/A	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.3001_3003delAACinsGAA	p.Asn1001Glu	missense	N/A	ENSP00000296137.2	Q9BQS8-1
	FYCO1	ENST00000874259.1		c.3001_3003delAACinsGAA	p.Asn1001Glu	missense	N/A	ENSP00000544318.1
	FYCO1	ENST00000965269.1		c.3001_3003delAACinsGAA	p.Asn1001Glu	missense	N/A	ENSP00000635328.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

GnomAD MNV AF: 0.120 AC: 33601 Hom.: 3175

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cataract 18 (1)
-	1	-	Developmental cataract (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71622515; hg19: chr3-46007823;