rs760832768

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_006885.4(ZFHX3):c.10841G>C(p.Arg3614Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,453,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R3614S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

ZFHX3
NM_006885.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.924

Publications

0 publications found

Variant links:

Genes affected

ZFHX3 (HGNC:777): (zinc finger homeobox 3) This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. Multiple transcript variants expressed from alternate promoters and encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ZFHX3 links:

ZFHX3-AS1 (HGNC:56033): (ZFHX3 antisense RNA 1)

ZFHX3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09989783).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000204 (26/127410) while in subpopulation AFR AF = 0.000569 (19/33382). AF 95% confidence interval is 0.000372. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006885.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFHX3	NM_006885.4	MANE Select	c.10841G>C	p.Arg3614Thr	missense	Exon 10 of 10	NP_008816.3
ZFHX3	NM_001386735.1		c.10841G>C	p.Arg3614Thr	missense	Exon 17 of 17	NP_001373664.1	Q15911-1
ZFHX3	NM_001164766.2		c.8099G>C	p.Arg2700Thr	missense	Exon 9 of 9	NP_001158238.1	Q15911-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.10841G>C	p.Arg3614Thr	missense	Exon 10 of 10	ENSP00000268489.5	Q15911-1
ZFHX3	ENST00000397992.5	TSL:1	c.8099G>C	p.Arg2700Thr	missense	Exon 9 of 9	ENSP00000438926.3	Q15911-2
ZFHX3	ENST00000641206.2		c.10841G>C	p.Arg3614Thr	missense	Exon 18 of 18	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

127410

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000569

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00114

GnomAD2 exomes

AF:

0.0000306

AC:

AN:

228950

AF XY:

0.0000240

show subpopulations

Gnomad AFR exome

AF:

0.000427

Gnomad AMR exome

AF:

0.0000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000981

AC:

AN:

1325596

Hom.:

Cov.:

AF XY:

0.00000913

AC XY:

AN XY:

657354

show subpopulations

African (AFR)

AF:

0.000338

AC:

AN:

29594

American (AMR)

AF:

0.0000505

AC:

AN:

39634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21012

East Asian (EAS)

AF:

0.00

AC:

AN:

30924

South Asian (SAS)

AF:

0.00

AC:

AN:

79772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5040

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1027146

Other (OTH)

AF:

0.0000194

AC:

AN:

51630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000204

AC:

AN:

127410

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

61188

show subpopulations

African (AFR)

AF:

0.000569

AC:

AN:

33382

American (AMR)

AF:

0.000393

AC:

AN:

12728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3200

East Asian (EAS)

AF:

0.00

AC:

AN:

4092

South Asian (SAS)

AF:

0.00

AC:

AN:

3692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60496

Other (OTH)

AF:

0.00114

AC:

AN:

1760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000676

Hom.:

Bravo

AF:

0.000200

ExAC

AF:

0.0000248

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.071

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.094

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.52

M_CAP

Benign

0.016

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

0.92

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.37

REVEL

Benign

0.16

Sift

Benign

0.18

Sift4G

Benign

0.58

Polyphen

0.12

Vest4

0.20

MVP

0.093

MPC

0.14

ClinPred

0.055

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.41

Mutation Taster

=69/31

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

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