16-6545897-G-C

Variant names:

• chr16-6545897-G-C
• rs17823421
• NM_018723.4:c.-63-108706G>C

Variant summary

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

The NM_018723.4(RBFOX1):​c.-63-108706G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,086 control chromosomes in the GnomAD database, including 8,012 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 0.30 (8012 hom., cov: 33)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.421
• Publications: 3 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	NM_018723.4	MANE Select	c.-63-108706G>C		intron	N/A	NP_061193.2
	RBFOX1	NM_001415887.1		c.535-108706G>C		intron	N/A	NP_001402816.1
	RBFOX1	NM_001415888.1		c.535-108706G>C		intron	N/A	NP_001402817.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	ENST00000550418.6	TSL:1 MANE Select	c.-63-108706G>C		intron	N/A	ENSP00000450031.1
	RBFOX1	ENST00000553186.5	TSL:1	c.-63-108706G>C		intron	N/A	ENSP00000447753.1
	RBFOX1	ENST00000551752.5	TSL:1	c.-64+61983G>C		intron	N/A	ENSP00000447281.1

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45692 AN: 151968 Hom.: 8013 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.347

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

GnomAD4 genome AF: 0.300 AC: 45695 AN: 152086 Hom.: 8012 Cov.: 33 AF XY: 0.298 AC XY: 22184 AN XY: 74330

African (AFR) AF: 0.121 AC: 5006 AN: 41520

American (AMR) AF: 0.302 AC: 4620 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1690 AN: 3472

East Asian (EAS) AF: 0.354 AC: 1818 AN: 5142

South Asian (SAS) AF: 0.309 AC: 1488 AN: 4810

European-Finnish (FIN) AF: 0.324 AC: 3425 AN: 10580

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26428 AN: 67966

Other (OTH) AF: 0.351 AC: 737 AN: 2102

Alfa AF: 0.180 Hom.: 415

Bravo AF: 0.292

Asia WGS AF: 0.383 AC: 1334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.47
DANN	Benign	0.51
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17823421; hg19: chr16-6595898;