dbSNP rs6542517: STEAP3:p.Gln450His (chr2-119257621-A-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000409811.5(STEAP3):c.1350A>T(p.Gln450His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,498,542 control chromosomes in the GnomAD database, including 1,640 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q450E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.065 ( 808 hom., cov: 32)

Exomes 𝑓: 0.018 ( 832 hom. )

Consequence

STEAP3
ENST00000409811.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.0620

Publications

4 publications found

Variant links:

Genes affected

STEAP3 (HGNC:24592): (STEAP3 metalloreductase) This gene encodes a multipass membrane protein that functions as an iron transporter. The encoded protein can reduce both iron (Fe3+) and copper (Cu2+) cations. This protein may mediate downstream responses to p53, including promoting apoptosis. Deficiency in this gene can cause anemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

STEAP3 links:

STEAP3-AS1 (HGNC:41053): (STEAP3 antisense RNA 1)

STEAP3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.162094E-4).

BP6

Variant 2-119257621-A-T is Benign according to our data. Variant chr2-119257621-A-T is described in ClinVar as Benign. ClinVar VariationId is 3056077.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STEAP3	NM_182915.3 link	c.1215+2773A>T		intron_variant	Intron 5 of 5	ENST00000393110.7	NP_878919.2	Q658P3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STEAP3	ENST00000393110.7 link	c.1215+2773A>T		intron_variant	Intron 5 of 5	1	NM_182915.3	ENSP00000376822.2		Q658P3-2

Frequencies

GnomAD3 genomes

AF:

0.0652

AC:

9917

AN:

152136

Hom.:

808

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.0385

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0447

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.0612

GnomAD2 exomes

AF:

0.0297

AC:

2872

AN:

96554

AF XY:

0.0296

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.0253

Gnomad ASJ exome

AF:

0.0529

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00243

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0312

GnomAD4 exome

AF:

0.0184

AC:

24710

AN:

1346288

Hom.:

832

Cov.:

AF XY:

0.0192

AC XY:

12701

AN XY:

662454

show subpopulations

African (AFR)

AF:

0.189

AC:

5447

AN:

28798

American (AMR)

AF:

0.0258

AC:

629

AN:

24382

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

1029

AN:

22450

East Asian (EAS)

AF:

0.0000611

AC:

AN:

32760

South Asian (SAS)

AF:

0.0477

AC:

3327

AN:

69704

European-Finnish (FIN)

AF:

0.00383

AC:

181

AN:

47266

Middle Eastern (MID)

AF:

0.0763

AC:

419

AN:

5492

European-Non Finnish (NFE)

AF:

0.0112

AC:

11827

AN:

1059686

Other (OTH)

AF:

0.0332

AC:

1849

AN:

55750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1232

2463

3695

4926

6158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

550

1100

1650

2200

2750

<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:

0.0652

AC:

9925

AN:

152254

Hom.:

808

Cov.:

AF XY:

0.0642

AC XY:

4782

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.187

AC:

7785

AN:

41524

American (AMR)

AF:

0.0384

AC:

587

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

157

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0443

AC:

214

AN:

4826

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0141

AC:

961

AN:

68022

Other (OTH)

AF:

0.0605

AC:

128

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

428

856

1283

1711

2139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0417

Hom.:

Bravo

AF:

0.0733

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00986

AC:

ExAC

AF:

0.0363

AC:

804

Asia WGS

AF:

0.0230

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

STEAP3-related disorder

Benign:1

Mar 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.0

(source)

DANN

Benign

0.84

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.25

MetaRNN

Benign

0.00072

MetaSVM

Benign

-0.91

PhyloP100

0.062

PROVEAN

Benign

-0.90

REVEL

Benign

0.024

Sift

Pathogenic

0.0

Sift4G

Benign

0.15

Polyphen

0.12

Vest4

0.064

MutPred

0.18

Loss of solvent accessibility (P = 0.1551);

ClinPred

0.0038

GERP RS

-0.40

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over