9-130617800-C-G

Variant names:

• chr9-130617800-C-G
• rs761470228
• NM_003934.2:c.571C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003934.2(FUBP3):​c.571C>G​(p.Arg191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R191W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FUBP3 NM_003934.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• Publications: 0 publications found

Genes affected

FUBP3 (HGNC:4005): (far upstream element binding protein 3) Enables single-stranded DNA binding activity. Involved in positive regulation of gene expression; positive regulation of transcription, DNA-templated; and transcription, DNA-templated. Acts upstream of or within positive regulation of transcription by RNA polymerase II. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003934.2. 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
	FUBP3	NM_003934.2	MANE Select	c.571C>G	p.Arg191Gly	missense	Exon 8 of 19	NP_003925.1	Q96I24-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUBP3	ENST00000319725.10	TSL:1 MANE Select	c.571C>G	p.Arg191Gly	missense	Exon 8 of 19	ENSP00000318177.9	Q96I24-1
	FUBP3	ENST00000964145.1		c.571C>G	p.Arg191Gly	missense	Exon 8 of 21	ENSP00000634204.1
	FUBP3	ENST00000936135.1		c.613C>G	p.Arg205Gly	missense	Exon 8 of 19	ENSP00000606194.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429702 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 713282

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32856

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082682

Other (OTH) AF: 0.00 AC: 0 AN: 59308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.60		Loss of MoRF binding (P = 0.0224)
MVP		0.77
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.90
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761470228; hg19: chr9-133493187;