rs6542517

Variant names:

• chr2-119257621-A-T
• rs6542517
• ENST00000409811.5:c.1350A>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_138637.3(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. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.065 (808 hom., cov: 32)
  • Exomes 𝑓: 0.018 (832 hom.)
• Consequence: STEAP3 NM_138637.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0620

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

ACMG classification

Verdict is Benign. Variant got -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 id 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	c.1215+2773A>T		intron_variant	Intron 5 of 5	ENST00000393110.7	NP_878919.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0652 AC: 9917 AN: 152136 Hom.: 808 Cov.: 32

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

GnomAD3 exomes AF: 0.0297 AC: 2872 AN: 96554 Hom.: 152 AF XY: 0.0296 AC XY: 1558 AN XY: 52712

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 SAS exome AF: 0.0497

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.: 31 AF XY: 0.0192 AC XY: 12701 AN XY: 662454

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.0258

Gnomad4 ASJ exome AF: 0.0458

Gnomad4 EAS exome AF: 0.0000611

Gnomad4 SAS exome AF: 0.0477

Gnomad4 FIN exome AF: 0.00383

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0332

GnomAD4 genome AF: 0.0652 AC: 9925 AN: 152254 Hom.: 808 Cov.: 32 AF XY: 0.0642 AC XY: 4782 AN XY: 74432

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.0384

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0443

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0417 Hom.: 83

Bravo AF: 0.0733

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00986 AC: 38

ExAC AF: 0.0363 AC: 804

Asia WGS AF: 0.0230 AC: 79 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

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
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.0
DANN	Benign	0.84
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.00072	T
MetaSVM	Benign	-0.91	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Polyphen		0.12	B
Vest4		0.064
MutPred		0.18		Loss of solvent accessibility (P = 0.1551);
ClinPred		0.0038	T
GERP RS		-0.40

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: rs6542517; hg19: chr2-120015197;