16-72787445-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3611L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 28)
  • Exomes 𝑓: 0.0080 (70 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.07

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

ACMG classification

Verdict is Benign. Variant got -16 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.
• BS2: High AC in GnomAd at 948 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4	c.10831C>T	p.His3611Tyr	missense_variant	10/10	ENST00000268489.10
ZFHX3-AS1	NR_171702.1	n.391-33328G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10	c.10831C>T	p.His3611Tyr	missense_variant	10/10	1	NM_006885.4	P1
ZFHX3-AS1	ENST00000687589.1	n.482+5626G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 948 AN: 151720 Hom.: 8 Cov.: 28

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.: 10 AF XY: 0.00700 AC XY: 901 AN XY: 128790

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.: 70 Cov.: 37 AF XY: 0.00788 AC XY: 5681 AN XY: 721234

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.: 8 Cov.: 28 AF XY: 0.00637 AC XY: 473 AN XY: 74214

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.: 7

Bravo AF: 0.00693

ESP6500AA AF: 0.00231 AC: 10

ESP6500EA AF: 0.00601 AC: 51

ExAC AF: 0.00721 AC: 873

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ZFHX3-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.043
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	0.98	D;N
PrimateAI	Uncertain	0.64	T
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	T
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

Other links and lift over

dbSNP: rs200992486; hg19: chr16-72821344;