Genetic Variant NM_006885.4:c.10872T>C (chr16-72787404-A-G) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_006885.4(ZFHX3):c.10872T>C(p.Ala3624Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,540,794 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00072 ( 11 hom. )

Consequence

ZFHX3
NM_006885.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.81

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 16-72787404-A-G is Benign according to our data. Variant chr16-72787404-A-G is described in ClinVar as [Benign]. Clinvar id is 2646811.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.81 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000416 (61/146682) while in subpopulation SAS AF= 0.00612 (27/4412). AF 95% confidence interval is 0.00432. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4 link	c.10872T>C	p.Ala3624Ala	synonymous_variant	Exon 10 of 10	ENST00000268489.10	NP_008816.3	Q15911-1Q8N2Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10 link	c.10872T>C	p.Ala3624Ala	synonymous_variant	Exon 10 of 10	1	NM_006885.4	ENSP00000268489.5		Q15911-1

Frequencies

GnomAD3 genomes

AF:

0.000416

AC:

AN:

146596

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000135

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00449

Gnomad SAS

AF:

0.00610

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000600

Gnomad OTH

AF:

0.000984

GnomAD3 exomes

AF:

0.00108

AC:

260

AN:

241514

Hom.:

AF XY:

0.00127

AC XY:

168

AN XY:

131844

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00426

Gnomad SAS exome

AF:

0.00517

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000120

Gnomad OTH exome

AF:

0.00154

GnomAD4 exome

AF:

0.000717

AC:

999

AN:

1394112

Hom.:

Cov.:

AF XY:

0.000863

AC XY:

598

AN XY:

692976

show subpopulations

Gnomad4 AFR exome

AF:

0.000417

Gnomad4 AMR exome

AF:

0.0000705

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0105

Gnomad4 SAS exome

AF:

0.00497

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000860

Gnomad4 OTH exome

AF:

0.00188

GnomAD4 genome

AF:

0.000416

AC:

AN:

146682

Hom.:

Cov.:

AF XY:

0.000574

AC XY:

AN XY:

71416

show subpopulations

Gnomad4 AFR

AF:

0.000125

Gnomad4 AMR

AF:

0.000134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00451

Gnomad4 SAS

AF:

0.00612

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000600

Gnomad4 OTH

AF:

0.000975

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000227

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ZFHX3-related disorder

Benign:1

Aug 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ZFHX3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.8

DANN

Benign

0.85

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