Genetic Variant USF2:p.Ala28Val (chr19-35269466-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003367.4(USF2):c.83C>T(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,547,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

USF2
NM_003367.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

USF2 (HGNC:12594): (upstream transcription factor 2, c-fos interacting) This gene encodes a member of the basic helix-loop-helix leucine zipper family of transcription factors. The encoded protein can activate transcription through pyrimidine-rich initiator (Inr) elements and E-box motifs and is involved in regulating multiple cellular processes. [provided by RefSeq, Mar 2016]

USF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017660826).

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USF2	NM_003367.4 link	c.83C>T	p.Ala28Val	missense_variant	Exon 2 of 10	ENST00000222305.8	NP_003358.1	Q15853-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USF2	ENST00000222305.8 link	c.83C>T	p.Ala28Val	missense_variant	Exon 2 of 10	1	NM_003367.4	ENSP00000222305.2		Q15853-1

Frequencies

GnomAD3 genomes

AF:

0.000180

AC:

AN:

150168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000342

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000193

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000462

AC:

AN:

173170

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

96720

show subpopulations

Gnomad AFR exome

AF:

0.000425

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:

0.0000636

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000178

AC:

249

AN:

1397264

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

113

AN XY:

693868

show subpopulations

Gnomad4 AFR exome

AF:

0.000205

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:

0.000216

Gnomad4 OTH exome

AF:

0.000139

GnomAD4 genome

AF:

0.000180

AC:

AN:

150276

Hom.:

Cov.:

AF XY:

0.0000817

AC XY:

AN XY:

73408

show subpopulations

Gnomad4 AFR

AF:

0.000341

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000193

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000126

AC:

ExAC

AF:

0.0000174

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83C>T (p.A28V) alteration is located in exon 2 (coding exon 2) of the USF2 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 to be replaced by a valine (V). 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

Benign

0.11

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.062

.;T;.;.;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.040

LIST_S2

Uncertain

0.86

D;D;D;D;D

MetaRNN

Benign

0.018

T;T;T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.14

N;N;N;N;.

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.59

N;N;.;N;.

REVEL

Benign

0.16

Sift

Benign

0.38

T;T;.;D;.

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.20

B;B;.;.;B

Vest4

0.17

MVP

0.20

MPC

0.81

ClinPred

0.059

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.071

gMVP

0.10

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

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