Variant 16-72787423-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006885.4(ZFHX3):c.10853C>T(p.Pro3618Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000605 in 1,602,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P3618P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

ZFHX3
NM_006885.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.71

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 made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4 linkuse as main transcript	c.10853C>T	p.Pro3618Leu	missense_variant	10/10	ENST00000268489.10
ZFHX3-AS1	NR_171702.1 linkuse as main transcript	n.391-33350G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10 linkuse as main transcript	c.10853C>T	p.Pro3618Leu	missense_variant	10/10	1	NM_006885.4	P1	Q15911-1
ZFHX3-AS1	ENST00000687589.1 linkuse as main transcript	n.482+5604G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000530

AC:

AN:

151076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000621

AC:

AN:

241694

Hom.:

AF XY:

0.0000836

AC XY:

AN XY:

131574

show subpopulations

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 SAS exome

AF:

0.000302

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000460

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000613

AC:

AN:

1451166

Hom.:

Cov.:

AF XY:

0.0000722

AC XY:

AN XY:

720546

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000316

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000462

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000530

AC:

AN:

151076

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

73760

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000211

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000591

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000582

Hom.:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.10853C>T (p.P3618L) alteration is located in exon 10 (coding exon 9) of the ZFHX3 gene. This alteration results from a C to T substitution at nucleotide position 10853, causing the proline (P) at amino acid position 3618 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

-0.050

Cadd

Uncertain

Dann

Benign

0.96

DEOGEN2

Benign

0.37

T;.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.94

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.0

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.0

D;D;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

0.98

D;.;D

Vest4

0.34

MVP

0.23

MPC

0.095

ClinPred

0.57

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over