chr16-7653930-G-T

Variant names:

• chr16-7653930-G-T
• rs761510301
• NM_018723.4:c.873G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_018723.4(RBFOX1):​c.873G>T​(p.Pro291Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P291P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RBFOX1 NM_018723.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.

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.873G>T	p.Pro291Pro	synonymous	Exon 12 of 16	NP_061193.2
	RBFOX1	NM_145893.3	MANE Plus Clinical	c.933G>T	p.Pro311Pro	synonymous	Exon 9 of 14	NP_665900.1
	RBFOX1	NM_001415887.1		c.1470G>T	p.Pro490Pro	synonymous	Exon 15 of 20	NP_001402816.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBFOX1	ENST00000550418.6	TSL:1 MANE Select	c.873G>T	p.Pro291Pro	synonymous	Exon 12 of 16	ENSP00000450031.1
	RBFOX1	ENST00000355637.9	TSL:1 MANE Plus Clinical	c.933G>T	p.Pro311Pro	synonymous	Exon 9 of 14	ENSP00000347855.4
	RBFOX1	ENST00000311745.9	TSL:1	c.933G>T	p.Pro311Pro	synonymous	Exon 9 of 13	ENSP00000309117.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 2 AN: 167316 AF XY: 0.0000213

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399082 Hom.: 0 Cov.: 35 AF XY: 0.00000433 AC XY: 3 AN XY: 692390

African (AFR) AF: 0.00 AC: 0 AN: 31668

American (AMR) AF: 0.0000264 AC: 1 AN: 37944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23224

East Asian (EAS) AF: 0.00 AC: 0 AN: 38110

South Asian (SAS) AF: 0.00 AC: 0 AN: 79818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4816

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1088132

Other (OTH) AF: 0.00 AC: 0 AN: 57942

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.6
DANN	Benign	0.82
PhyloP100		-1.2
PromoterAI		-0.039	Neutral

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: rs761510301; hg19: chr16-7703932;