NM_003410.4:c.911A>G

Variant names:

• chrX-24207826-A-G
• rs200720278
• NM_003410.4:c.911A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_003410.4(ZFX):​c.911A>G​(p.Asn304Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,209,622 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 129 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N304I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00034 (0 hom. 116 hem.)
• Consequence: ZFX NM_003410.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67
• Publications: 1 publications found

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

ENSG00000304417 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.1463 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder, X-linked, syndromic 37.
• BP4: Computational evidence support a benign effect (MetaRNN=0.059246242).
• BS2: High Hemizygotes in GnomAd4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFX	NM_003410.4	MANE Select	c.911A>G	p.Asn304Ser	missense	Exon 7 of 10	NP_003401.2	P17010-1
	ZFX	NM_001330327.2		c.1028A>G	p.Asn343Ser	missense	Exon 8 of 11	NP_001317256.1	P17010-3
	ZFX	NM_001178084.2		c.911A>G	p.Asn304Ser	missense	Exon 5 of 8	NP_001171555.1	P17010-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFX	ENST00000304543.10	TSL:5 MANE Select	c.911A>G	p.Asn304Ser	missense	Exon 7 of 10	ENSP00000304985.5	P17010-1
	ZFX	ENST00000379177.5	TSL:1	c.911A>G	p.Asn304Ser	missense	Exon 8 of 11	ENSP00000368475.1	P17010-1
	ZFX	ENST00000539115.5	TSL:1	c.224A>G	p.Asn75Ser	missense	Exon 3 of 6	ENSP00000438233.1	P17010-2

Frequencies

GnomAD3 genomes AF: 0.000304 AC: 34 AN: 111835 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.000333

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000564

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000362 AC: 66 AN: 182537 AF XY: 0.000373

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000438

Gnomad NFE exome AF: 0.000673

Gnomad OTH exome AF: 0.000887

GnomAD4 exome AF: 0.000342 AC: 375 AN: 1097732 Hom.: 0 Cov.: 31 AF XY: 0.000319 AC XY: 116 AN XY: 363108

African (AFR) AF: 0.000152 AC: 4 AN: 26393

American (AMR) AF: 0.0000285 AC: 1 AN: 35112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 53894

European-Finnish (FIN) AF: 0.000493 AC: 20 AN: 40527

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4136

European-Non Finnish (NFE) AF: 0.000394 AC: 332 AN: 842030

Other (OTH) AF: 0.000347 AC: 16 AN: 46083

GnomAD4 genome AF: 0.000304 AC: 34 AN: 111890 Hom.: 0 Cov.: 23 AF XY: 0.000382 AC XY: 13 AN XY: 34064

African (AFR) AF: 0.00 AC: 0 AN: 30837

American (AMR) AF: 0.0000951 AC: 1 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.000372 AC: 1 AN: 2691

European-Finnish (FIN) AF: 0.000333 AC: 2 AN: 6002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000564 AC: 30 AN: 53215

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.000407 Hom.: 17

Bravo AF: 0.000227

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000546

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.076
Sift	Benign	0.29	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.21
MVP		0.35
MPC		0.89
ClinPred		0.050	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.86
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200720278; hg19: chrX-24225943;