rs3735478

Variant names:

• chr7-44760577-G-T
• rs3735478
• NM_031449.4:c.1224G>T

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 32 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031449.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMIZ2	NM_031449.4	MANE Select	c.1224G>T	p.Leu408Phe	missense	Exon 9 of 19	NP_113637.3
	ZMIZ2	NM_174929.2		c.1146G>T	p.Leu382Phe	missense	Exon 7 of 17	NP_777589.2
	ZMIZ2	NM_001300959.2		c.1050G>T	p.Leu350Phe	missense	Exon 8 of 18	NP_001287888.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZMIZ2	ENST00000309315.9	TSL:2 MANE Select	c.1224G>T	p.Leu408Phe	missense	Exon 9 of 19	ENSP00000311778.4
	ZMIZ2	ENST00000441627.5	TSL:1	c.1224G>T	p.Leu408Phe	missense	Exon 8 of 18	ENSP00000414723.1
	ZMIZ2	ENST00000413916.5	TSL:1	c.1050G>T	p.Leu350Phe	missense	Exon 8 of 18	ENSP00000409648.1

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

GnomAD2 exomes AF: 0.246 AC: 61348 AN: 249486 AF XY: 0.247

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 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

African (AFR) AF: 0.0455 AC: 1523 AN: 33480

American (AMR) AF: 0.205 AC: 9188 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5306 AN: 26128

East Asian (EAS) AF: 0.128 AC: 5082 AN: 39700

South Asian (SAS) AF: 0.178 AC: 15335 AN: 86252

European-Finnish (FIN) AF: 0.441 AC: 23544 AN: 53402

Middle Eastern (MID) AF: 0.193 AC: 1115 AN: 5768

European-Non Finnish (NFE) AF: 0.290 AC: 322563 AN: 1111980

Other (OTH) AF: 0.256 AC: 15457 AN: 60388

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

African (AFR) AF: 0.0542 AC: 2244 AN: 41438

American (AMR) AF: 0.206 AC: 3144 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 690 AN: 3466

East Asian (EAS) AF: 0.127 AC: 657 AN: 5168

South Asian (SAS) AF: 0.173 AC: 833 AN: 4810

European-Finnish (FIN) AF: 0.449 AC: 4710 AN: 10490

Middle Eastern (MID) AF: 0.197 AC: 57 AN: 290

European-Non Finnish (NFE) AF: 0.289 AC: 19640 AN: 67898

Other (OTH) AF: 0.220 AC: 464 AN: 2108

Alfa AF: 0.251 Hom.: 16623

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 v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.75
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.028	D
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.39
MutPred		0.067		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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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