rs375940495

Variant names:

• chr17-79106740-C-G
• rs375940495
• NM_001350451.2:c.271G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-79106740-C-G
• chr17-79106740-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001350451.2(RBFOX3):​c.271G>C​(p.Asp91His) variant causes a missense change. The variant allele was found at a frequency of 0.000000731 in 1,368,280 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D91E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RBFOX3 NM_001350451.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• Publications: 0 publications found

Genes affected

RBFOX3 (HGNC:27097): (RNA binding fox-1 homolog 3) This gene encodes a member of the RNA-binding FOX protein family which is involved in the regulation of alternative splicing of pre-mRNA. The protein has an N-terminal proline-rich region, an RNA recognition motif (RRM) domain, and a C-terminal alanine-rich region. This gene produces the neuronal nuclei (NeuN) antigen that has been widely used as a marker for post-mitotic neurons. This gene has its highest expression in the central nervous system and plays a prominent role in neural tissue development and regulation of adult brain function. Mutations in this gene have been associated with numerous neurological disorders. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2017]

RBFOX3 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBFOX3	NM_001350451.2	c.271G>C	p.Asp91His	missense_variant	Exon 6 of 15	ENST00000693108.1	NP_001337380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBFOX3	ENST00000693108.1	c.271G>C	p.Asp91His	missense_variant	Exon 6 of 15		NM_001350451.2	ENSP00000510395.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1368280 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 674520

African (AFR) AF: 0.00 AC: 0 AN: 29368

American (AMR) AF: 0.00 AC: 0 AN: 29558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24152

East Asian (EAS) AF: 0.00 AC: 0 AN: 32944

South Asian (SAS) AF: 0.00 AC: 0 AN: 74888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1066886

Other (OTH) AF: 0.00 AC: 0 AN: 56712

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	31
DANN	Benign	0.94
DEOGEN2	Benign	0.062	.;.;.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.8	.;.;.;L;L
PhyloP100		7.2
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	0.080	T;.;T;T;T
Polyphen		0.99	.;.;.;D;.
Vest4		0.21
MutPred		0.21		.;.;Gain of catalytic residue at D91 (P = 0.0166);Gain of catalytic residue at D91 (P = 0.0166);Gain of catalytic residue at D91 (P = 0.0166);
MVP		0.69
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.50
gMVP		0.51
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs375940495; hg19: chr17-77102822;