dbSNP rs2248913: ZFHX4:c.3511+145T>C (chr8-76842916-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_024721.5(ZFHX4):c.3511+145T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 507,072 control chromosomes in the GnomAD database, including 13,783 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 3434 hom., cov: 32)

Exomes 𝑓: 0.22 ( 10349 hom. )

Consequence

ZFHX4
NM_024721.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.424

Publications

2 publications found

Variant links:

Genes affected

ZFHX4 (HGNC:30939): (zinc finger homeobox 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZFHX4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, Broad Center for Mendelian Genomics
complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
orofacial cleft
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
ptosis, hereditary congenital, 1
Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ZFHX4 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 (BayesDel_noAF=-0.44).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX4	NM_024721.5 link	c.3511+145T>C		intron_variant	Intron 6 of 10	ENST00000651372.2	NP_078997.4	Q86UP3-5
ZFHX4	NM_001410934.1 link	c.3433+145T>C		intron_variant	Intron 6 of 10		NP_001397863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX4	ENST00000651372.2 link	c.3511+145T>C		intron_variant	Intron 6 of 10		NM_024721.5	ENSP00000498627.1		Q86UP3-5

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

29215

AN:

152006

Hom.:

3434

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0758

Gnomad AMI

AF:

0.282

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.0403

Gnomad SAS

AF:

0.261

Gnomad FIN

AF:

0.288

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.262

Gnomad OTH

AF:

0.185

GnomAD4 exome

AF:

0.221

AC:

78271

AN:

354948

Hom.:

10349

AF XY:

0.222

AC XY:

40949

AN XY:

184164

show subpopulations

African (AFR)

AF:

0.0769

AC:

826

AN:

10746

American (AMR)

AF:

0.122

AC:

1806

AN:

14794

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

1984

AN:

10252

East Asian (EAS)

AF:

0.0344

AC:

919

AN:

26702

South Asian (SAS)

AF:

0.234

AC:

6107

AN:

26100

European-Finnish (FIN)

AF:

0.261

AC:

7250

AN:

27788

Middle Eastern (MID)

AF:

0.186

AC:

582

AN:

3122

European-Non Finnish (NFE)

AF:

0.253

AC:

54516

AN:

215540

Other (OTH)

AF:

0.215

AC:

4281

AN:

19904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

2775

5550

8324

11099

13874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.192

AC:

29220

AN:

152124

Hom.:

3434

Cov.:

AF XY:

0.193

AC XY:

14357

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0756

AC:

3139

AN:

41522

American (AMR)

AF:

0.153

AC:

2333

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

700

AN:

3470

East Asian (EAS)

AF:

0.0402

AC:

208

AN:

5170

South Asian (SAS)

AF:

0.260

AC:

1257

AN:

4826

European-Finnish (FIN)

AF:

0.288

AC:

3042

AN:

10568

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.262

AC:

17844

AN:

67984

Other (OTH)

AF:

0.188

AC:

398

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1157

2315

3472

4630

5787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.222

Hom.:

1656

Bravo

AF:

0.174

Asia WGS

AF:

0.153

AC:

534

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.42

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over