Genetic Variant NM_003410.4:c.192C>A (chrX-24179316-C-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_003410.4(ZFX):c.192C>A(p.Ile64Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00699 in 1,210,160 control chromosomes in the GnomAD database, including 42 homozygotes. There are 2,709 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 2 hom., 165 hem., cov: 22)

Exomes 𝑓: 0.0071 ( 40 hom. 2544 hem. )

Consequence

ZFX
NM_003410.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.96

Publications

0 publications found

Variant links:

Genes affected

ZFX (HGNC:12869): (zinc finger protein X-linked) This gene on the X chromosome is structurally similar to a related gene on the Y chromosome. It encodes a member of the krueppel C2H2-type zinc-finger protein family. The full-length protein contains an acidic transcriptional activation domain (AD), a nuclear localization sequence (NLS) and a DNA binding domain (DBD) consisting of 13 C2H2-type zinc fingers. Studies in mouse embryonic and adult hematopoietic stem cells showed that this gene was required as a transcriptional regulator for self-renewal of both stem cell types, but it was dispensable for growth and differentiation of their progeny. Multiple alternatively spliced transcript variants encoding different isoforms have been identified, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2010]

ZFX Gene-Disease associations (from GenCC):

X-linked syndromic complex neurodevelopmental disorder
Inheritance: XL Classification: STRONG Submitted by: ClinGen
intellectual developmental disorder, X-linked, syndromic 37
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ZFX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant X-24179316-C-A is Benign according to our data. Variant chrX-24179316-C-A is described in ClinVar as Benign. ClinVar VariationId is 711679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.96 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003410.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFX	NM_003410.4	MANE Select	c.192C>A	p.Ile64Ile	synonymous	Exon 5 of 10	NP_003401.2	P17010-1
ZFX	NM_001330327.2		c.309C>A	p.Ile103Ile	synonymous	Exon 6 of 11	NP_001317256.1	P17010-3
ZFX	NM_001178084.2		c.192C>A	p.Ile64Ile	synonymous	Exon 3 of 8	NP_001171555.1	P17010-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFX	ENST00000304543.10	TSL:5 MANE Select	c.192C>A	p.Ile64Ile	synonymous	Exon 5 of 10	ENSP00000304985.5	P17010-1
ZFX	ENST00000379177.5	TSL:1	c.192C>A	p.Ile64Ile	synonymous	Exon 6 of 11	ENSP00000368475.1	P17010-1
ZFX	ENST00000539115.5	TSL:1	c.-41-28010C>A		intron	N/A	ENSP00000438233.1	P17010-2

Frequencies

GnomAD3 genomes

AF:

0.00567

AC:

635

AN:

111932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000975

Gnomad AMI

AF:

0.0456

Gnomad AMR

AF:

0.00256

Gnomad ASJ

AF:

0.0618

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000369

Gnomad FIN

AF:

0.000498

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.00688

Gnomad OTH

AF:

0.00730

GnomAD2 exomes

AF:

0.00640

AC:

1174

AN:

183482

AF XY:

0.00604

show subpopulations

Gnomad AFR exome

AF:

0.000456

Gnomad AMR exome

AF:

0.00339

Gnomad ASJ exome

AF:

0.0641

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000437

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.00817

GnomAD4 exome

AF:

0.00713

AC:

7825

AN:

1098177

Hom.:

Cov.:

AF XY:

0.00700

AC XY:

2544

AN XY:

363535

show subpopulations

African (AFR)

AF:

0.000606

AC:

AN:

26401

American (AMR)

AF:

0.00364

AC:

128

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

1201

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.000462

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.000790

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00556

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00712

AC:

5996

AN:

842069

Other (OTH)

AF:

0.00876

AC:

404

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

309

617

926

1234

1543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.00566

AC:

634

AN:

111983

Hom.:

Cov.:

AF XY:

0.00483

AC XY:

165

AN XY:

34183

show subpopulations

African (AFR)

AF:

0.000973

AC:

AN:

30826

American (AMR)

AF:

0.00256

AC:

AN:

10549

Ashkenazi Jewish (ASJ)

AF:

0.0618

AC:

164

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3600

South Asian (SAS)

AF:

0.000370

AC:

AN:

2702

European-Finnish (FIN)

AF:

0.000498

AC:

AN:

6026

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00688

AC:

366

AN:

53204

Other (OTH)

AF:

0.00721

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0137

Hom.:

111

Bravo

AF:

0.00587

EpiCase

AF:

0.00736

EpiControl

AF:

0.00859

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

8.0

(source)

DANN

Benign

0.74

PhyloP100

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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