rs2290477

Positions:

• chr3-113655786-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001009899.4(USF3):​c.5896G>T​(p.Ala1966Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,614,054 control chromosomes in the GnomAD database, including 1,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1966V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (117 hom., cov: 32)
  • Exomes 𝑓: 0.023 (924 hom.)
• Consequence: USF3 NM_001009899.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013995767).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USF3	NM_001009899.4	c.5896G>T	p.Ala1966Ser	missense_variant	7/7	ENST00000316407.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USF3	ENST00000316407.9	c.5896G>T	p.Ala1966Ser	missense_variant	7/7	5	NM_001009899.4	P2
USF3	ENST00000491165.5	c.257-5936G>T		intron_variant		1		A2
USF3	ENST00000496826.1	n.5850G>T		non_coding_transcript_exon_variant	3/3	1
USF3	ENST00000478658.1	c.5896G>T	p.Ala1966Ser	missense_variant	5/5	5		P2

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3627 AN: 152170 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0487

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0868

Gnomad FIN AF: 0.0645

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0444 AC: 11052 AN: 248978 Hom.: 446 AF XY: 0.0434 AC XY: 5867 AN XY: 135058

Gnomad AFR exome AF: 0.00452

Gnomad AMR exome AF: 0.0942

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.0803

Gnomad FIN exome AF: 0.0659

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0336

GnomAD4 exome AF: 0.0227 AC: 33147 AN: 1461766 Hom.: 924 Cov.: 34 AF XY: 0.0241 AC XY: 17557 AN XY: 727176

Gnomad4 AFR exome AF: 0.00317

Gnomad4 AMR exome AF: 0.0856

Gnomad4 ASJ exome AF: 0.00960

Gnomad4 EAS exome AF: 0.0923

Gnomad4 SAS exome AF: 0.0782

Gnomad4 FIN exome AF: 0.0660

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0250

GnomAD4 genome AF: 0.0238 AC: 3617 AN: 152288 Hom.: 117 Cov.: 32 AF XY: 0.0278 AC XY: 2071 AN XY: 74456

Gnomad4 AFR AF: 0.00464

Gnomad4 AMR AF: 0.0485

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0862

Gnomad4 FIN AF: 0.0645

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0174 Hom.: 117

Bravo AF: 0.0214

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00473 AC: 20

ESP6500EA AF: 0.0123 AC: 104

ExAC AF: 0.0412 AC: 4987

Asia WGS AF: 0.0740 AC: 258 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0103

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.88
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.54	T;.
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.031
Sift	Benign	0.41	T;T
Sift4G	Benign	0.64	T;T
Vest4		0.023
MPC		0.087
ClinPred		0.00075	T
GERP RS		3.7
gMVP		0.097

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

LitVar

Other links and lift over

dbSNP: rs2290477; hg19: chr3-113374633; COSMIC: COSV57072101;