2-119245726-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_182915.3(STEAP3):c.260A>G(p.Gln87Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000243 in 1,614,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: STEAP3 NM_182915.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.28

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034532577).
• BS2: High AC in GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STEAP3	NM_182915.3	c.260A>G	p.Gln87Arg	missense_variant	3/6	ENST00000393110.7
STEAP3-AS1	NR_046721.1	n.1914T>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STEAP3	ENST00000393110.7	c.260A>G	p.Gln87Arg	missense_variant	3/6	1	NM_182915.3
STEAP3-AS1	ENST00000654197.1	n.1316T>C		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251148 Hom.: 1 AF XY: 0.000206 AC XY: 28 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000781

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: 0.000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461868 Hom.: 1 Cov.: 31 AF XY: 0.000245 AC XY: 178 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000218

EpiControl AF: 0.000178

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

Apr 12, 2022

The c.260A>G (p.Q87R) alteration is located in exon 3 (coding exon 2) of the STEAP3 gene. This alteration results from a A to G substitution at nucleotide position 260, causing the glutamine (Q) at amino acid position 87 to be replaced by an arginine (R). 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

Dec 05, 2023

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 77 of the STEAP3 protein (p.Gln77Arg). This variant is present in population databases (rs200273960, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 2364119). 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.049
Eigen_PC	Benign	0.090
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T;.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.51	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.84	P;B;D;B
Vest4		0.36
MVP		0.57
MPC		0.18
ClinPred		0.19	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.19
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200273960; hg19: chr2-120003302; COSMIC: COSV61530231;