rs2274257

Variant names:

• chr1-77963723-G-C
• rs2274257
• NM_003902.5:c.1042-8C>G

Variant summary

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

The NM_003902.5(FUBP1):​c.1042-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0858 in 1,592,650 control chromosomes in the GnomAD database, including 7,084 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (834 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6250 hom.)
• Consequence: FUBP1 NM_003902.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001518
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0200
• Publications: 11 publications found

Genes affected

FUBP1 (HGNC:4004): (far upstream element binding protein 1) The protein encoded by this gene is a single stranded DNA-binding protein that binds to multiple DNA elements, including the far upstream element (FUSE) located upstream of c-myc. Binding to FUSE occurs on the non-coding strand, and is important to the regulation of c-myc in undifferentiated cells. This protein contains three domains, an amphipathic helix N-terminal domain, a DNA-binding central domain, and a C-terminal transactivation domain that contains three tyrosine-rich motifs. The N-terminal domain is thought to repress the activity of the C-terminal domain. This protein is also thought to bind RNA, and contains 3'-5' helicase activity with in vitro activity on both DNA-DNA and RNA-RNA duplexes. Aberrant expression of this gene has been found in malignant tissues, and this gene is important to neural system and lung development. Binding of this protein to viral RNA is thought to play a role in several viral diseases, including hepatitis C and hand, foot and mouth disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-77963723-G-C is Benign according to our data. Variant chr1-77963723-G-C is described in ClinVar as Benign. ClinVar VariationId is 402886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUBP1	NM_003902.5	c.1042-8C>G		splice_region_variant, intron_variant	Intron 12 of 19	ENST00000370768.7	NP_003893.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUBP1	ENST00000370768.7	c.1042-8C>G		splice_region_variant, intron_variant	Intron 12 of 19	1	NM_003902.5	ENSP00000359804.2

Frequencies

GnomAD3 genomes AF: 0.0910 AC: 13835 AN: 152070 Hom.: 827 Cov.: 32

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.0862

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0798

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.115 AC: 26778 AN: 233514 AF XY: 0.112

Gnomad AFR exome AF: 0.0513

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.0934

Gnomad EAS exome AF: 0.0889

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.0827

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.0853 AC: 122811 AN: 1440464 Hom.: 6250 Cov.: 28 AF XY: 0.0860 AC XY: 61627 AN XY: 716734

African (AFR) AF: 0.0498 AC: 1607 AN: 32238

American (AMR) AF: 0.233 AC: 9322 AN: 39998

Ashkenazi Jewish (ASJ) AF: 0.0898 AC: 2248 AN: 25028

East Asian (EAS) AF: 0.0785 AC: 3099 AN: 39462

South Asian (SAS) AF: 0.114 AC: 9448 AN: 82754

European-Finnish (FIN) AF: 0.147 AC: 7828 AN: 53186

Middle Eastern (MID) AF: 0.0809 AC: 458 AN: 5658

European-Non Finnish (NFE) AF: 0.0757 AC: 83439 AN: 1102606

Other (OTH) AF: 0.0901 AC: 5362 AN: 59534

GnomAD4 genome AF: 0.0911 AC: 13859 AN: 152186 Hom.: 834 Cov.: 32 AF XY: 0.0979 AC XY: 7283 AN XY: 74404

African (AFR) AF: 0.0517 AC: 2146 AN: 41538

American (AMR) AF: 0.184 AC: 2808 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 321 AN: 3464

East Asian (EAS) AF: 0.0862 AC: 447 AN: 5186

South Asian (SAS) AF: 0.111 AC: 537 AN: 4826

European-Finnish (FIN) AF: 0.171 AC: 1812 AN: 10584

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0798 AC: 5427 AN: 68010

Other (OTH) AF: 0.102 AC: 216 AN: 2110

Alfa AF: 0.0840 Hom.: 188

Bravo AF: 0.0910

Asia WGS AF: 0.121 AC: 418 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.64
DANN	Benign	0.52
PhyloP100		-0.020
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.010
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: rs2274257; hg19: chr1-78429408; COSMIC: COSV53925539;