Genetic Variant NM_018723.4:c.-127+39228T>C (chr16-6059220-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018723.4(RBFOX1):c.-127+39228T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 151,992 control chromosomes in the GnomAD database, including 23,441 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.55 ( 23441 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

RBFOX1
NM_018723.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.915

Publications

7 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:

ENSG00000257180 (HGNC:):

ENSG00000257180 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_018723.4 link	c.-127+39228T>C		intron_variant	Intron 1 of 15	ENST00000550418.6	NP_061193.2	Q9NWB1-1Q59HD3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6 link	c.-127+39228T>C		intron_variant	Intron 1 of 15	1	NM_018723.4	ENSP00000450031.1		Q9NWB1-1

Frequencies

GnomAD3 genomes

AF:

0.547

AC:

83114

AN:

151872

Hom.:

23439

Cov.:

show subpopulations

Gnomad AFR

AF:

0.402

Gnomad AMI

AF:

0.711

Gnomad AMR

AF:

0.593

Gnomad ASJ

AF:

0.542

Gnomad EAS

AF:

0.597

Gnomad SAS

AF:

0.547

Gnomad FIN

AF:

0.573

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.616

Gnomad OTH

AF:

0.550

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.547

AC:

83151

AN:

151990

Hom.:

23441

Cov.:

AF XY:

0.545

AC XY:

40470

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.401

AC:

16624

AN:

41438

American (AMR)

AF:

0.594

AC:

9076

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.542

AC:

1878

AN:

3468

East Asian (EAS)

AF:

0.597

AC:

3073

AN:

5150

South Asian (SAS)

AF:

0.548

AC:

2638

AN:

4816

European-Finnish (FIN)

AF:

0.573

AC:

6049

AN:

10552

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.616

AC:

41855

AN:

67970

Other (OTH)

AF:

0.551

AC:

1160

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1894

3788

5683

7577

9471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

722

1444

2166

2888

3610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.591

Hom.:

13122

Bravo

AF:

0.544

Asia WGS

AF:

0.546

AC:

1900

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.92

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over