rs3735478

chr7-44760577-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031449.4(ZMIZ2):c.1224G>T(p.Leu408Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,632 control chromosomes in the GnomAD database, including 62,384 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (4521 hom., cov: 30)
  • Exomes 𝑓: 0.27 (57863 hom.)
• Consequence: ZMIZ2 NM_031449.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.748

Genes affected

ZMIZ2 (HGNC:22229): (zinc finger MIZ-type containing 2) ZMIZ2 and ZMIZ1 (MIM 607159) are members of a PIAS (see MIM 603566)-like family of proteins that interact with nuclear hormone receptors. ZMIZ2 interacts with androgen receptor (AR; MIM 313700) and enhances AR-mediated transcription (Huang et al., 2005 [PubMed 16051670]).[supplied by OMIM, May 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003502369).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMIZ2	NM_031449.4	c.1224G>T	p.Leu408Phe	missense_variant	9/19	ENST00000309315.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMIZ2	ENST00000309315.9	c.1224G>T	p.Leu408Phe	missense_variant	9/19	2	NM_031449.4	P1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32590 AN: 151700 Hom.: 4517 Cov.: 30

Gnomad AFR AF: 0.0543

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.246 AC: 61348 AN: 249486 Hom.: 8799 AF XY: 0.247 AC XY: 33414 AN XY: 135354

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.273 AC: 399113 AN: 1461814 Hom.: 57863 Cov.: 36 AF XY: 0.271 AC XY: 196727 AN XY: 727212

Gnomad4 AFR exome AF: 0.0455

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.441

Gnomad4 NFE exome AF: 0.290

Gnomad4 OTH exome AF: 0.256

GnomAD4 genome AF: 0.215 AC: 32600 AN: 151818 Hom.: 4521 Cov.: 30 AF XY: 0.220 AC XY: 16286 AN XY: 74150

Gnomad4 AFR AF: 0.0542

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.449

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.220

Alfa AF: 0.262 Hom.: 11940

Bravo AF: 0.190

TwinsUK AF: 0.286 AC: 1060

ALSPAC AF: 0.295 AC: 1138

ESP6500AA AF: 0.0550 AC: 232

ESP6500EA AF: 0.276 AC: 2344

ExAC AF: 0.241 AC: 29187

Asia WGS AF: 0.164 AC: 570 AN: 3478

EpiCase AF: 0.283

EpiControl AF: 0.274

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;.;T;T;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.00060	P;P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;.
REVEL	Benign	0.10
Sift	Uncertain	0.028	D;D;D;D;D;.
Sift4G	Benign	0.25	T;T;T;T;T;T
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.39
MutPred		0.067		.;Loss of stability (P = 0.0257);Loss of stability (P = 0.0257);.;.;Loss of stability (P = 0.0257);
MPC		0.50
ClinPred		0.037	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
gMVP		0.24

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: rs3735478; hg19: chr7-44800176; COSMIC: COSV54806046; COSMIC: COSV54806046;