Variant 19-24126693-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_203282.4(ZNF254):c.693T>G(p.Ile231Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,613,360 control chromosomes in the GnomAD database, including 4 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 0.00071 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

ZNF254
NM_203282.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.14

Variant links:

Genes affected

ZNF254 (HGNC:13047): (zinc finger protein 254) Zinc finger proteins have been shown to interact with nucleic acids and to have diverse functions. The zinc finger domain is a conserved amino acid sequence motif containing 2 specifically positioned cysteines and 2 histidines that are involved in coordinating zinc. Kruppel-related proteins form 1 family of zinc finger proteins. See ZFP93 (MIM 604749) for additional information on zinc finger proteins.[supplied by OMIM, Jul 2002]

ZNF254 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010181963).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF254	NM_203282.4 linkuse as main transcript	c.693T>G	p.Ile231Met	missense_variant	4/4	ENST00000357002.5	NP_975011.3	O75437-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF254	ENST00000357002.5 linkuse as main transcript	c.693T>G	p.Ile231Met	missense_variant	4/4	1	NM_203282.4	ENSP00000349494.3	O75437-1
ZNF254	ENST00000613065.4 linkuse as main transcript	c.570T>G	p.Ile190Met	missense_variant	5/5	3		ENSP00000482703.1	A0A087WZJ7
ZNF254	ENST00000611359.3 linkuse as main transcript	c.474T>G	p.Ile158Met	missense_variant	3/3	3		ENSP00000483222.1	A0A087X0A2
ZNF254	ENST00000616028.2 linkuse as main transcript	c.438T>G	p.Ile146Met	missense_variant	2/2	4		ENSP00000484930.1	F5H2M4

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000822

AC:

205

AN:

249492

Hom.:

AF XY:

0.000807

AC XY:

109

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.000314

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.000417

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.00117

AC:

1713

AN:

1461160

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

847

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.00145

Gnomad4 OTH exome

AF:

0.000845

GnomAD4 genome

AF:

0.000710

AC:

108

AN:

152200

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00127

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000983

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00114

AC:

139

EpiCase

AF:

0.00120

EpiControl

AF:

0.00130

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

The c.693T>G (p.I231M) alteration is located in exon 4 (coding exon 4) of the ZNF254 gene. This alteration results from a T to G substitution at nucleotide position 693, causing the isoleucine (I) at amino acid position 231 to be replaced by a methionine (M). 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

0.080

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0071

.;.;.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.67

T;T;T;T

M_CAP

Benign

0.0013

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

.;.;.;M

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.1

.;.;.;N

REVEL

Benign

0.12

Sift

Uncertain

0.0010

.;.;.;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.99

.;.;.;D

Vest4

0.21

MVP

0.12

MPC

0.0032

ClinPred

0.054

GERP RS

-0.039

Varity_R

0.15

gMVP

0.0013

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

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