16-6483548-C-A

Variant names:

• chr16-6483548-C-A
• rs7187508
• NM_018723.4:c.-64+166491C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001415889.1(RBFOX1):​c.45+4C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 1,534,700 control chromosomes in the GnomAD database, including 253,723 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29558 hom., cov: 31)
  • Exomes 𝑓: 0.56 (224165 hom.)
• Consequence: RBFOX1 NM_001415889.1 splice_region, intron
• Scores: Splicing: ADA: 0.00003166
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.24
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 16-6483548-C-A is Benign according to our data. Variant chr16-6483548-C-A is described in ClinVar as Benign. ClinVar VariationId is 803210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001415889.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	NM_018723.4	MANE Select	c.-64+166491C>A		intron	N/A	NP_061193.2
	RBFOX1	NM_001415887.1		c.534+166491C>A		intron	N/A	NP_001402816.1
	RBFOX1	NM_001415888.1		c.534+166491C>A		intron	N/A	NP_001402817.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	ENST00000550418.6	TSL:1 MANE Select	c.-64+166491C>A		intron	N/A	ENSP00000450031.1	Q9NWB1-1
	RBFOX1	ENST00000553186.5	TSL:1	c.-64+166491C>A		intron	N/A	ENSP00000447753.1	Q9NWB1-3
	RBFOX1	ENST00000547605.5	TSL:1	c.-64+166491C>A		intron	N/A	ENSP00000450402.1	F8VR27

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93296 AN: 151690 Hom.: 29522 Cov.: 31

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.790

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.626

GnomAD2 exomes AF: 0.518 AC: 66528 AN: 128324 AF XY: 0.516

Gnomad AFR exome AF: 0.768

Gnomad AMR exome AF: 0.424

Gnomad ASJ exome AF: 0.605

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.565 AC: 780718 AN: 1382896 Hom.: 224165 Cov.: 52 AF XY: 0.560 AC XY: 382358 AN XY: 682330

African (AFR) AF: 0.763 AC: 24109 AN: 31586

American (AMR) AF: 0.440 AC: 15709 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 15142 AN: 25176

East Asian (EAS) AF: 0.313 AC: 11177 AN: 35714

South Asian (SAS) AF: 0.439 AC: 34810 AN: 79214

European-Finnish (FIN) AF: 0.553 AC: 18461 AN: 33412

Middle Eastern (MID) AF: 0.607 AC: 3455 AN: 5688

European-Non Finnish (NFE) AF: 0.579 AC: 624918 AN: 1078550

Other (OTH) AF: 0.569 AC: 32937 AN: 57868

GnomAD4 genome AF: 0.615 AC: 93372 AN: 151804 Hom.: 29558 Cov.: 31 AF XY: 0.606 AC XY: 44958 AN XY: 74142

African (AFR) AF: 0.757 AC: 31367 AN: 41446

American (AMR) AF: 0.538 AC: 8216 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2138 AN: 3468

East Asian (EAS) AF: 0.347 AC: 1767 AN: 5088

South Asian (SAS) AF: 0.430 AC: 2062 AN: 4794

European-Finnish (FIN) AF: 0.544 AC: 5715 AN: 10512

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.587 AC: 39874 AN: 67916

Other (OTH) AF: 0.625 AC: 1319 AN: 2110

Alfa AF: 0.570 Hom.: 4109

Bravo AF: 0.619

Asia WGS AF: 0.429 AC: 1495 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Idiopathic generalized epilepsy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.74
PhyloP100		2.2
PromoterAI		0.041	Neutral
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0080

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

Other links and lift over

dbSNP: rs7187508; hg19: chr16-6533549;