3-113655292-A-C

Position:

• chr3-113655292-A-C

Variant summary

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

The NM_001009899.4(USF3):​c.6390T>G​(p.Phe2130Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: USF3 NM_001009899.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

Genes affected

USF3 (HGNC:30494): (upstream transcription factor family member 3) This gene encodes a large protein that contains a helix-loop-helix domain and a polyglutamine region. A deletion in the polyglutamine region was associated with risk for thyroid carcinoma. [provided by RefSeq, May 2017]

USF3 (HGNC:):

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
USF3	NM_001009899.4	c.6390T>G	p.Phe2130Leu	missense_variant	7/7	ENST00000316407.9	NP_001009899.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USF3	ENST00000316407.9	c.6390T>G	p.Phe2130Leu	missense_variant	7/7	5	NM_001009899.4	ENSP00000320794.4
USF3	ENST00000491165.5	c.257-5442T>G		intron_variant		1		ENSP00000420752.1
USF3	ENST00000496826.1	n.6344T>G		non_coding_transcript_exon_variant	3/3	1
USF3	ENST00000478658.1	c.6390T>G	p.Phe2130Leu	missense_variant	5/5	5		ENSP00000420721.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 28, 2022

The c.6390T>G (p.F2130L) alteration is located in exon 7 (coding exon 5) of the USF3 gene. This alteration results from a T to G substitution at nucleotide position 6390, causing the phenylalanine (F) at amino acid position 2130 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.071	T;T
Vest4		0.94
MutPred		0.21		Gain of catalytic residue at F2130 (P = 0.0143);Gain of catalytic residue at F2130 (P = 0.0143);
MVP		0.093
MPC		0.52
ClinPred		0.84	D
GERP RS		0.31
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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.

Other links and lift over

hg19: chr3-113374139;