chr7-88283093-T-C

Variant names:

• chr7-88283093-T-C
• rs372107775
• NM_024636.4:c.532A>G

Variant summary

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

The NM_024636.4(STEAP4):​c.532A>G​(p.Met178Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000839 in 1,608,746 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (4 hom.)
• Consequence: STEAP4 NM_024636.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.897

Genes affected

STEAP4 (HGNC:21923): (STEAP4 metalloreductase) The protein encoded by this gene belongs to the STEAP (six transmembrane epithelial antigen of prostate) family, and resides in the golgi apparatus. It functions as a metalloreductase that has the ability to reduce both Fe(3+) to Fe(2+) and Cu(2+) to Cu(1+), using NAD(+) as acceptor. Studies in mice and human suggest that this gene maybe involved in adipocyte development and metabolism, and may contribute to the normal biology of the prostate cell, as well as prostate cancer progression. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2011]

ENSG00000228113 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026000828).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STEAP4	NM_024636.4	c.532A>G	p.Met178Val	missense_variant	Exon 3 of 5	ENST00000380079.9	NP_078912.2
STEAP4	NM_001205315.2	c.532A>G	p.Met178Val	missense_variant	Exon 4 of 6		NP_001192244.1
STEAP4	NM_001205316.2	c.456+721A>G		intron_variant	Intron 2 of 3		NP_001192245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STEAP4	ENST00000380079.9	c.532A>G	p.Met178Val	missense_variant	Exon 3 of 5	1	NM_024636.4	ENSP00000369419.4

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000741 AC: 18 AN: 242816 Hom.: 0 AF XY: 0.0000531 AC XY: 7 AN XY: 131748

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000509

Gnomad SAS exome AF: 0.0000342

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.000342

GnomAD4 exome AF: 0.0000783 AC: 114 AN: 1456542 Hom.: 4 Cov.: 31 AF XY: 0.0000676 AC XY: 49 AN XY: 724476

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0000352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000981

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74356

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00115

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.000526 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000745 AC: 9

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.532A>G (p.M178V) alteration is located in exon 3 (coding exon 2) of the STEAP4 gene. This alteration results from a A to G substitution at nucleotide position 532, causing the methionine (M) at amino acid position 178 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.092
DANN	Benign	0.48
DEOGEN2	Benign	0.0014	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.5	N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.055
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.080
MVP		0.14
MPC		0.21
ClinPred		0.0046	T
GERP RS		-10
Varity_R		0.17
gMVP		0.42

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: rs372107775; hg19: chr7-87912408;