16-7518249-C-G

Position:

• chr16-7518249-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018723.4(RBFOX1):​c.130C>G​(p.Pro44Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RBFOX1 NM_018723.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.41

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3541057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBFOX1	NM_018723.4	c.130C>G	p.Pro44Ala	missense_variant	5/16	ENST00000550418.6	NP_061193.2
RBFOX1	NM_145893.3	c.190C>G	p.Pro64Ala	missense_variant	2/14	ENST00000355637.9	NP_665900.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBFOX1	ENST00000550418.6	c.130C>G	p.Pro44Ala	missense_variant	5/16	1	NM_018723.4	ENSP00000450031.1
RBFOX1	ENST00000355637.9	c.190C>G	p.Pro64Ala	missense_variant	2/14	1	NM_145893.3	ENSP00000347855.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251290 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135800

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;.;.;T;.;T;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	.;.;M;M;.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.
REVEL	Benign	0.12
Sift	Benign	0.048	.;D;D;D;D;D;D;D;D;D;T;T;T;D;.;.
Sift4G	Benign	0.17	.;T;T;T;T;T;D;T;T;T;T;T;T;T;T;T
Polyphen		0.59, 0.80, 0.86, 0.80, 0.63, 0.066, 0.80, 0.84	.;.;P;P;P;P;P;.;.;P;B;P;P;.;.;.
Vest4		0.54, 0.64, 0.62, 0.56, 0.56, 0.63, 0.65, 0.57, 0.56, 0.60, 0.55, 0.63
MutPred		0.29		.;.;.;.;Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);.;.;.;.;.;.;.;.;.;.;
MVP		0.12
MPC		0.016
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.29
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs201490398; hg19: chr16-7568251;