Genetic Variant NM_152695.6:c.899A>G (chrX-135360418-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_152695.6(ZNF449):c.899A>G(p.Glu300Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,209,528 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000032 ( 0 hom. 16 hem. )

Consequence

ZNF449
NM_152695.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.188

Publications

0 publications found

Variant links:

Genes affected

ZNF449 (HGNC:21039): (zinc finger protein 449) This gene encodes a nuclear protein that likely functions as a transcription factor. The protein includes an N-terminal SCAN domain, and seven C2H2-type zinc finger motifs. [provided by RefSeq, May 2010]

ZNF449 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06061122).

BP6

Variant X-135360418-A-G is Benign according to our data. Variant chrX-135360418-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2661487.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 16 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152695.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF449	NM_152695.6	MANE Select	c.899A>G	p.Glu300Gly	missense	Exon 5 of 5	NP_689908.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF449	ENST00000339249.5	TSL:1 MANE Select	c.899A>G	p.Glu300Gly	missense	Exon 5 of 5	ENSP00000339585.4	Q6P9G9-1
ZNF449	ENST00000850984.1		c.899A>G	p.Glu300Gly	missense	Exon 5 of 5	ENSP00000521066.1
ZNF449	ENST00000887114.1		c.899A>G	p.Glu300Gly	missense	Exon 5 of 5	ENSP00000557173.1

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111730

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000658

AC:

AN:

182269

AF XY:

0.0000596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000983

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000319

AC:

AN:

1097798

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

363278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26365

American (AMR)

AF:

0.000114

AC:

AN:

35124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19350

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0000356

AC:

AN:

841971

Other (OTH)

AF:

0.0000217

AC:

AN:

46079

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33934

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30692

American (AMR)

AF:

0.00

AC:

AN:

10558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2663

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6131

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53053

Other (OTH)

AF:

0.00

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.083

M_CAP

Benign

0.0038

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PhyloP100

-0.19

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.59

REVEL

Benign

0.068

Sift

Benign

0.11

Sift4G

Benign

0.38

Polyphen

0.0020

Vest4

0.096

MutPred

0.34

Gain of glycosylation at T298 (P = 0.1343)

MVP

0.48

MPC

0.82

ClinPred

0.028

GERP RS

4.4

Varity_R

0.098

gMVP

0.50

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over