16-5526411-C-T

Variant names:

• chr16-5526411-C-T
• rs4548867
• ENST00000641259.1:c.258+59157C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000641259.1(RBFOX1):​c.258+59157C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 151,776 control chromosomes in the GnomAD database, including 14,082 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 0.41 (14082 hom., cov: 32)
• Consequence: RBFOX1 ENST00000641259.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.125
• Publications: 1 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX1	NM_001415887.1	c.378+59157C>T		intron_variant	Intron 2 of 19		NP_001402816.1
RBFOX1	NM_001415888.1	c.378+59157C>T		intron_variant	Intron 2 of 17		NP_001402817.1
RBFOX1	XM_017023318.3	c.378+59157C>T		intron_variant	Intron 2 of 19		XP_016878807.1
RBFOX1	XM_024450303.2	c.340-72491C>T		intron_variant	Intron 1 of 18		XP_024306071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000641259.1	c.258+59157C>T		intron_variant	Intron 2 of 19			ENSP00000493041.1
RBFOX1	ENST00000585867.2	c.258+59157C>T		intron_variant	Intron 2 of 2	2		ENSP00000493140.1
RBFOX1	ENST00000569895.3	n.343+59157C>T		intron_variant	Intron 2 of 6	3

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61882 AN: 151656 Hom.: 14069 Cov.: 32

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.356

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.408 AC: 61940 AN: 151776 Hom.: 14082 Cov.: 32 AF XY: 0.413 AC XY: 30637 AN XY: 74182

African (AFR) AF: 0.480 AC: 19844 AN: 41348

American (AMR) AF: 0.416 AC: 6347 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1487 AN: 3462

East Asian (EAS) AF: 0.958 AC: 4932 AN: 5148

South Asian (SAS) AF: 0.620 AC: 2981 AN: 4808

European-Finnish (FIN) AF: 0.264 AC: 2783 AN: 10534

Middle Eastern (MID) AF: 0.345 AC: 100 AN: 290

European-Non Finnish (NFE) AF: 0.329 AC: 22351 AN: 67922

Other (OTH) AF: 0.393 AC: 830 AN: 2110

Alfa AF: 0.371 Hom.: 1413

Bravo AF: 0.422

Asia WGS AF: 0.774 AC: 2689 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.8
DANN	Benign	0.39
PhyloP100		-0.13

Splicing

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

Other links and lift over

dbSNP: rs4548867; hg19: chr16-5576412;