Genetic Variant NM_080678.3:c.442A>G (chr2-238032252-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080678.3(UBE2F):c.442A>G(p.Thr148Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000617 in 1,459,748 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

UBE2F
NM_080678.3 missense, splice_region

Scores

Splicing: ADA: 0.04518

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.25

Variant links:

Genes affected

UBE2F (HGNC:12480): (ubiquitin conjugating enzyme E2 F (putative)) Enables NEDD8 conjugating enzyme activity. Involved in protein neddylation. Predicted to be located in cytosol. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

UBE2F links:

UBE2F-SCLY (HGNC:48339): (UBE2F-SCLY readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring UBE2F (ubiquitin-conjugating enzyme E2F) and SCLY (selenocysteine lyase) genes on chromosome 2. The read-through transcript is a candidate for non-sense mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

UBE2F-SCLY links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
UBE2F	NM_080678.3 link	c.442A>G	p.Thr148Ala	missense_variant, splice_region_variant	Exon 8 of 10	ENST00000272930.9	NP_542409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE2F	ENST00000272930.9 link	c.442A>G	p.Thr148Ala	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_080678.3	ENSP00000272930.4		Q969M7-1
UBE2F-SCLY	ENST00000449191.1 link	n.283-3626A>G		intron_variant	Intron 5 of 10	3		ENSP00000456827.1		H3BSR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250752

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135550

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459748

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726388

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.442A>G (p.T148A) alteration is located in exon 8 (coding exon 7) of the UBE2F gene. This alteration results from a A to G substitution at nucleotide position 442, causing the threonine (T) at amino acid position 148 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.;T;.;.;.;T;T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;D;T;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.52

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

L;.;.;L;.;.;.;L;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D;D;.;D

REVEL

Benign

0.26

Sift

Benign

0.091

T;D;T;T;T;D;T;.;T

Sift4G

Benign

0.19

T;T;T;T;T;T;T;T;T

Polyphen

0.89

P;D;.;.;.;.;.;P;.

Vest4

0.59

MutPred

0.49

Gain of catalytic residue at T148 (P = 0.0782);.;.;Gain of catalytic residue at T148 (P = 0.0782);.;.;Gain of catalytic residue at T148 (P = 0.0782);Gain of catalytic residue at T148 (P = 0.0782);.;

MVP

0.55

MPC

1.4

ClinPred

0.96

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.045

dbscSNV1_RF

Benign

0.40

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over