dbSNP rs2290477: USF3:p.Ala1966Ser (chr3-113655786-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.024 ( 117 hom., cov: 32)

Exomes 𝑓: 0.023 ( 924 hom. )

Consequence

USF3
NM_001009899.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.99

Publications

11 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

USF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009899.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USF3	NM_001009899.4	MANE Select	c.5896G>T	p.Ala1966Ser	missense	Exon 7 of 7	NP_001009899.3	Q68DE3
	USF3	NR_111981.2		n.664-5936G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USF3	ENST00000316407.9	TSL:5 MANE Select	c.5896G>T	p.Ala1966Ser	missense	Exon 7 of 7	ENSP00000320794.4	Q68DE3
USF3	ENST00000491165.5	TSL:1	c.257-5936G>T		intron	N/A	ENSP00000420752.1	C9JBW0
USF3	ENST00000496826.1	TSL:1	n.5850G>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3627

AN:

152170

Hom.:

117

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0444

AC:

11052

AN:

248978

AF XY:

0.0434

show subpopulations

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 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.:

AF XY:

0.0241

AC XY:

17557

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00317

AC:

106

AN:

33480

American (AMR)

AF:

0.0856

AC:

3827

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00960

AC:

251

AN:

26134

East Asian (EAS)

AF:

0.0923

AC:

3663

AN:

39694

South Asian (SAS)

AF:

0.0782

AC:

6741

AN:

86234

European-Finnish (FIN)

AF:

0.0660

AC:

3524

AN:

53404

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0121

AC:

13468

AN:

1111968

Other (OTH)

AF:

0.0250

AC:

1511

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1978

3957

5935

7914

9892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

646

1292

1938

2584

3230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0238

AC:

3617

AN:

152288

Hom.:

117

Cov.:

AF XY:

0.0278

AC XY:

2071

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00464

AC:

193

AN:

41556

American (AMR)

AF:

0.0485

AC:

742

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.111

AC:

573

AN:

5176

South Asian (SAS)

AF:

0.0862

AC:

416

AN:

4824

European-Finnish (FIN)

AF:

0.0645

AC:

685

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0137

AC:

931

AN:

68028

Other (OTH)

AF:

0.0161

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

168

336

503

671

839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0176

Hom.:

218

Bravo

AF:

0.0214

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00473

AC:

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.88

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0014

MetaSVM

Benign

-0.97

PhyloP100

2.0

PrimateAI

Benign

0.37

PROVEAN

Benign

0.31

REVEL

Benign

0.031

Sift

Benign

0.41

Sift4G

Benign

0.64

Vest4

0.023

MPC

0.087

ClinPred

0.00075

GERP RS

3.7

gMVP

0.097

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over