1-161041845-G-A

Position:

• chr1-161041845-G-A

Variant summary

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

The ENST00000368021.7(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 ENST00000368021.7 missense, splice_region
• Scores: Splicing: ADA: 0.9706
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

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]

ACMG classification

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	Protein	UniProt
USF1	NM_007122.5	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	6/11	ENST00000368021.7	NP_009053.1
USF1	NM_001276373.2	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	6/11		NP_001263302.1
USF1	NM_207005.3	c.101C>T	p.Ala34Val	missense_variant, splice_region_variant	6/11		NP_996888.1
USF1	XM_047429959.1	c.101C>T	p.Ala34Val	missense_variant, splice_region_variant	3/8		XP_047285915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USF1	ENST00000368021.7	c.278C>T	p.Ala93Val	missense_variant, splice_region_variant	6/11	1	NM_007122.5	ENSP00000357000	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454916 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722288

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.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
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	D
LIST_S2	Benign	0.81	.;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.5	L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
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	D
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

Other links and lift over

dbSNP: rs867308902; hg19: chr1-161011635; COSMIC: COSV105182378; COSMIC: COSV105182378;