Genetic Variant USF2:p.His62Leu (chr19-35269656-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003367.4(USF2):c.185A>T(p.His62Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

USF2
NM_003367.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37965855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USF2	NM_003367.4 link	c.185A>T	p.His62Leu	missense_variant	Exon 3 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.185A>T	p.His62Leu	missense_variant	Exon 3 of 10	1	NM_003367.4	ENSP00000222305.2		Q15853-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1382682

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

687076

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:

0.00000188

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.185A>T (p.H62L) alteration is located in exon 3 (coding exon 3) of the USF2 gene. This alteration results from a A to T substitution at nucleotide position 185, causing the histidine (H) at amino acid position 62 to be replaced by a leucine (L). 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

0.33

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.36

.;T;.;.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Uncertain

-0.047

MutationAssessor

Benign

1.8

L;L;L;L;.

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.8

D;N;.;N;.

REVEL

Uncertain

0.59

Sift

Benign

0.036

D;T;.;T;.

Sift4G

Uncertain

0.041

D;T;T;T;T

Polyphen

0.23

B;P;.;.;P

Vest4

0.37

MutPred

0.37

.;.;.;.;Gain of stability (P = 0.0227);

MVP

0.65

MPC

1.8

ClinPred

0.97

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over