Genetic Variant ZMIZ2:p.Ala184Val (chr7-44757560-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031449.4(ZMIZ2):c.551C>T(p.Ala184Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,589,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

ZMIZ2
NM_031449.4 missense, splice_region

Scores

Splicing: ADA: 0.9863

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.27

Variant links:

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]

ZMIZ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMIZ2	NM_031449.4 link	c.551C>T	p.Ala184Val	missense_variant, splice_region_variant	Exon 5 of 19	ENST00000309315.9	NP_113637.3	Q8NF64-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMIZ2	ENST00000309315.9 link	c.551C>T	p.Ala184Val	missense_variant, splice_region_variant	Exon 5 of 19	2	NM_031449.4	ENSP00000311778.4		Q8NF64-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000818

AC:

AN:

219968

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

122450

show subpopulations

Gnomad AFR exome

AF:

0.0000759

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000159

Gnomad NFE exome

AF:

0.000145

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000207

AC:

298

AN:

1437324

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

138

AN XY:

711784

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.000158

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000982

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000583

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.551C>T (p.A184V) alteration is located in exon 5 (coding exon 4) of the ZMIZ2 gene. This alteration results from a C to T substitution at nucleotide position 551, causing the alanine (A) at amino acid position 184 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

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;T;T;T;.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;.;D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.16

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;L;L;.;L;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.5

N;N;N;N;N;.

REVEL

Benign

0.091

Sift

Benign

0.064

T;T;T;T;T;.

Sift4G

Benign

0.28

T;T;T;T;T;T

Polyphen

0.85

P;B;B;.;P;.

Vest4

0.60

MVP

0.043

MPC

0.39

ClinPred

0.13

GERP RS

4.9

Varity_R

0.12

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over