16-7703759-T-G

Variant names:

• chr16-7703759-T-G
• rs12448737
• NM_018723.4:c.996-5297T>G

Variant summary

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

The NM_018723.4(RBFOX1):​c.996-5297T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 152,028 control chromosomes in the GnomAD database, including 15,081 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 0.44 (15081 hom., cov: 33)
• Consequence: RBFOX1 NM_018723.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 9 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

ENSG00000301273 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 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.996-5297T>G		intron	N/A	NP_061193.2
	RBFOX1	NM_145893.3	MANE Plus Clinical	c.1112-5297T>G		intron	N/A	NP_665900.1
	RBFOX1	NM_001415887.1		c.1646-5297T>G		intron	N/A	NP_001402816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	ENST00000550418.6	TSL:1 MANE Select	c.996-5297T>G		intron	N/A	ENSP00000450031.1
	RBFOX1	ENST00000355637.9	TSL:1 MANE Plus Clinical	c.1112-5297T>G		intron	N/A	ENSP00000347855.4
	RBFOX1	ENST00000311745.9	TSL:1	c.1059-5297T>G		intron	N/A	ENSP00000309117.5

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66887 AN: 151908 Hom.: 15075 Cov.: 33

Gnomad AFR AF: 0.451

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.440 AC: 66925 AN: 152028 Hom.: 15081 Cov.: 33 AF XY: 0.438 AC XY: 32543 AN XY: 74316

African (AFR) AF: 0.451 AC: 18697 AN: 41468

American (AMR) AF: 0.389 AC: 5953 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1940 AN: 3470

East Asian (EAS) AF: 0.152 AC: 785 AN: 5166

South Asian (SAS) AF: 0.444 AC: 2138 AN: 4820

European-Finnish (FIN) AF: 0.491 AC: 5174 AN: 10542

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.452 AC: 30699 AN: 67968

Other (OTH) AF: 0.435 AC: 915 AN: 2104

Alfa AF: 0.442 Hom.: 46886

Bravo AF: 0.430

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.17
DANN	Benign	0.60
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs12448737; hg19: chr16-7753761;