1-224157682-GA-TT

Variant names:

• chr1-224157682-GA-TT
• NM_015176.4:c.1043_1044delGAinsTT
• FBXO28 p.Arg348Leu

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Very_Strong PM5

The NM_015176.4(FBXO28):​c.1043_1044delGAinsTT​(p.Arg348Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R348G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBXO28 NM_015176.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.78
• Publications: 0 publications found

Genes affected

FBXO28 (HGNC:29046): (F-box protein 28) Members of the F-box protein family, such as FBXO28, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

FBXO28 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy 100

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_015176.4 (FBXO28) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-224157681-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1343398.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015176.4. 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
	FBXO28	NM_015176.4	MANE Select	c.1043_1044delGAinsTT	p.Arg348Leu	missense	N/A	NP_055991.1	Q9NVF7-1
	FBXO28	NM_001136115.3		c.*307_*308delGAinsTT		3_prime_UTR	Exon 4 of 4	NP_001129587.1	Q9NVF7-2
	FBXO28	NR_049764.2		n.923_924delGAinsTT		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO28	ENST00000366862.10	TSL:1 MANE Select	c.1043_1044delGAinsTT	p.Arg348Leu	missense	N/A	ENSP00000355827.5	Q9NVF7-1
	FBXO28	ENST00000424254.6	TSL:1	c.*307_*308delGAinsTT		3_prime_UTR	Exon 4 of 4	ENSP00000416888.2	Q9NVF7-2
	FBXO28	ENST00000523990.1	TSL:2	n.*523_*524delGAinsTT		non_coding_transcript_exon	Exon 4 of 4	ENSP00000430632.1	B4E0H5

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-224345384;