chr3-113655786-C-A

Variant names:

• chr3-113655786-C-A
• rs2290477
• NM_001009899.4:c.5896G>T

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• Publications: 11 publications found

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)

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USF3	NM_001009899.4	c.5896G>T	p.Ala1966Ser	missense_variant	Exon 7 of 7	ENST00000316407.9	NP_001009899.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USF3	ENST00000316407.9	c.5896G>T	p.Ala1966Ser	missense_variant	Exon 7 of 7	5	NM_001009899.4	ENSP00000320794.4
USF3	ENST00000496826.1	n.5850G>T		non_coding_transcript_exon_variant	Exon 3 of 3	1
USF3	ENST00000491165.5	c.257-5936G>T		intron_variant	Intron 6 of 6	1		ENSP00000420752.1
USF3	ENST00000478658.1	c.5896G>T	p.Ala1966Ser	missense_variant	Exon 5 of 5	5		ENSP00000420721.1

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

GnomAD2 exomes AF: 0.0444 AC: 11052 AN: 248978 AF XY: 0.0434

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.: 34 AF XY: 0.0241 AC XY: 17557 AN XY: 727176

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: 56 AN: 5768

European-Non Finnish (NFE) AF: 0.0121 AC: 13468 AN: 1111968

Other (OTH) AF: 0.0250 AC: 1511 AN: 60392

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

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: 40 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: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 931 AN: 68028

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.0176 Hom.: 218

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
PhyloP100		2.0
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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