2-119245887-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_182915.3(STEAP3):c.421G>A(p.Glu141Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000347 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: STEAP3 NM_182915.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.73

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STEAP3	NM_182915.3	c.421G>A	p.Glu141Lys	missense_variant	3/6	ENST00000393110.7
STEAP3-AS1	NR_046721.1	n.1753C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STEAP3	ENST00000393110.7	c.421G>A	p.Glu141Lys	missense_variant	3/6	1	NM_182915.3
STEAP3-AS1	ENST00000654197.1	n.1155C>T		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251180 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135762

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1461740 Hom.: 1 Cov.: 31 AF XY: 0.000330 AC XY: 240 AN XY: 727168

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74486

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000512 Hom.: 1

Bravo AF: 0.000506

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.421G>A (p.E141K) alteration is located in exon 3 (coding exon 2) of the STEAP3 gene. This alteration results from a G to A substitution at nucleotide position 421, causing the glutamic acid (E) at amino acid position 141 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 23, 2023

This variant has not been reported in the literature in individuals affected with STEAP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 2352607). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is present in population databases (rs181208641, gnomAD 0.04%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 131 of the STEAP3 protein (p.Glu131Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.017	D;D;T;D
Polyphen		0.99	D;P;D;P
Vest4		0.78
MVP		0.54
MPC		0.70
ClinPred		0.82	D
GERP RS		5.2
Varity_R		0.60
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs181208641; hg19: chr2-120003463; COSMIC: COSV100713545;