Genetic Variant RBFOX1:p.Ala327_Ala328dup (chr16-7676816-A-ACTGCCG) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The NM_018723.4(RBFOX1):c.979_984dupGCTGCC(p.Ala327_Ala328dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00000137 in 1,461,026 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RBFOX1
NM_018723.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.89

Publications

1 publications found

Variant links:

Genes affected

RBFOX1 (HGNC:18222): (RNA binding fox-1 homolog 1) The Fox-1 family of RNA-binding proteins is evolutionarily conserved, and regulates tissue-specific alternative splicing in metazoa. Fox-1 recognizes a (U)GCAUG stretch in regulated exons or in flanking introns. The protein binds to the C-terminus of ataxin-2 and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

RBFOX1 Gene-Disease associations (from GenCC):

epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P
autism susceptibility 1
Inheritance: Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine

RBFOX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_018723.4.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018723.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBFOX1	NM_018723.4	MANE Select	c.979_984dupGCTGCC	p.Ala327_Ala328dup	conservative_inframe_insertion	Exon 14 of 16	NP_061193.2
RBFOX1	NM_145893.3	MANE Plus Clinical	c.1042_1047dupGCTGCC	p.Ala348_Ala349dup	conservative_inframe_insertion	Exon 11 of 14	NP_665900.1	Q9NWB1-5
RBFOX1	NM_001415887.1		c.1576_1581dupGCTGCC	p.Ala526_Ala527dup	conservative_inframe_insertion	Exon 17 of 20	NP_001402816.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RBFOX1	ENST00000550418.6	TSL:1 MANE Select	c.979_984dupGCTGCC	p.Ala327_Ala328dup	conservative_inframe_insertion	Exon 14 of 16	ENSP00000450031.1	Q9NWB1-1
RBFOX1	ENST00000355637.9	TSL:1 MANE Plus Clinical	c.1042_1047dupGCTGCC	p.Ala348_Ala349dup	conservative_inframe_insertion	Exon 11 of 14	ENSP00000347855.4	Q9NWB1-5
RBFOX1	ENST00000311745.9	TSL:1	c.1042_1047dupGCTGCC	p.Ala348_Ala349dup	conservative_inframe_insertion	Exon 11 of 13	ENSP00000309117.5	Q9NWB1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461026

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726730

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111352

Other (OTH)

AF:

0.00

AC:

AN:

60348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.9

Mutation Taster

=57/43

polymorphism

(source)

Splicing

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

Publications

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16-7676816-ACTGCCG-ACTGCCGCTGCCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over