16-72787445-G-A

Position:

chr16-72787445-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006885.4(ZFHX3):c.10831C>T(p.His3611Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00786 in 1,604,088 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 8 hom., cov: 28)

Exomes 𝑓: 0.0080 ( 70 hom. )

Consequence

ZFHX3
NM_006885.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.07

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062671006).

BP6

Variant 16-72787445-G-A is Benign according to our data. Variant chr16-72787445-G-A is described in ClinVar as [Benign]. Clinvar id is 769903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00627 (952/151832) while in subpopulation AMR AF= 0.0132 (202/15274). AF 95% confidence interval is 0.0117. There are 8 homozygotes in gnomad4. There are 473 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High AC in GnomAd4 at 952 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFHX3	NM_006885.4 link	c.10831C>T	p.His3611Tyr	missense_variant	10/10	ENST00000268489.10	NP_008816.3	Q15911-1Q8N2Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10 link	c.10831C>T	p.His3611Tyr	missense_variant	10/10	1	NM_006885.4	ENSP00000268489.5		Q15911-1

Frequencies

GnomAD3 genomes

AF:

0.00625

AC:

948

AN:

151720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00281

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00505

Gnomad SAS

AF:

0.00606

Gnomad FIN

AF:

0.000756

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.00791

Gnomad OTH

AF:

0.00817

GnomAD3 exomes

AF:

0.00724

AC:

1707

AN:

235666

Hom.:

AF XY:

0.00700

AC XY:

901

AN XY:

128790

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.00148

Gnomad EAS exome

AF:

0.00606

Gnomad SAS exome

AF:

0.00556

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00810

Gnomad OTH exome

AF:

0.00713

GnomAD4 exome

AF:

0.00803

AC:

11661

AN:

1452256

Hom.:

Cov.:

AF XY:

0.00788

AC XY:

5681

AN XY:

721234

show subpopulations

Gnomad4 AFR exome

AF:

0.00243

Gnomad4 AMR exome

AF:

0.0144

Gnomad4 ASJ exome

AF:

0.00155

Gnomad4 EAS exome

AF:

0.00777

Gnomad4 SAS exome

AF:

0.00535

Gnomad4 FIN exome

AF:

0.00134

Gnomad4 NFE exome

AF:

0.00867

Gnomad4 OTH exome

AF:

0.00787

GnomAD4 genome

AF:

0.00627

AC:

952

AN:

151832

Hom.:

Cov.:

AF XY:

0.00637

AC XY:

473

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.00280

Gnomad4 AMR

AF:

0.0132

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00507

Gnomad4 SAS

AF:

0.00606

Gnomad4 FIN

AF:

0.000756

Gnomad4 NFE

AF:

0.00791

Gnomad4 OTH

AF:

0.00855

Alfa

AF:

0.00704

Hom.:

Bravo

AF:

0.00693

ESP6500AA

AF:

0.00231

AC:

ESP6500EA

AF:

0.00601

AC:

ExAC

AF:

0.00721

AC:

873

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ZFHX3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.11

T;.;T

Eigen

Benign

-0.043

Eigen_PC

Benign

0.025

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.71

.;T;T

MetaRNN

Benign

0.0063

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;L

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.059

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.051

T;T;.

Polyphen

0.67

P;.;P

Vest4

0.43

MVP

0.043

MPC

0.11

ClinPred

0.096

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.18

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