Variant 1-161041845-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_007122.5(USF1):c.278C>T(p.Ala93Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000687 in 1,454,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

USF1
NM_007122.5 missense, splice_region

Scores

Splicing: ADA: 0.9706

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.80

Variant links:

Genes affected

USF1 (HGNC:12593): (upstream transcription factor 1) This gene encodes a member of the basic helix-loop-helix leucine zipper family, and can function as a cellular transcription factor. The encoded protein can activate transcription through pyrimidine-rich initiator (Inr) elements and E-box motifs. This gene has been linked to familial combined hyperlipidemia (FCHL). Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been defined on chromosome 21. [provided by RefSeq, Feb 2013]

USF1 links:

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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/exons	MANE
USF1	NM_007122.5 linkuse as main transcript	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	6/11	ENST00000368021.7
USF1	NM_001276373.2 linkuse as main transcript	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	6/11
USF1	NM_207005.3 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant, splice_region_variant	6/11
USF1	XM_047429959.1 linkuse as main transcript	c.101C>T	p.Ala34Val	missense_variant, splice_region_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USF1	ENST00000368021.7 linkuse as main transcript	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	6/11	1	NM_007122.5	P1	P22415-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454916

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722288

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:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

The c.278C>T (p.A93V) alteration is located in exon 6 (coding exon 5) of the USF1 gene. This alteration results from a C to T substitution at nucleotide position 278, causing the alanine (A) at amino acid position 93 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

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D;.;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.66

D;D;D;D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.5

L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.96

N;N;N;N;D

REVEL

Uncertain

0.64

Sift

Benign

0.055

T;T;T;T;D

Sift4G

Benign

0.33

T;T;T;.;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.53

MutPred

0.38

Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;

MVP

0.98

MPC

1.7

ClinPred

0.95

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.81

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