rs7193297

chr16-72959932-A-Cchr16-72959932-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006885.4(ZFHX3):c.214T>G(p.Ser72Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,596,348 control chromosomes in the GnomAD database, including 140,363 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. S72S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.48 (18891 hom., cov: 32)
  • Exomes 𝑓: 0.40 (121472 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.6056085E-6).
• BP6: Variant 16-72959932-A-C is Benign according to our data. Variant chr16-72959932-A-C is described in ClinVar as [Benign]. Clinvar id is 3060596.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4	c.214T>G	p.Ser72Ala	missense_variant	2/10	ENST00000268489.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10	c.214T>G	p.Ser72Ala	missense_variant	2/10	1	NM_006885.4	P1
ZFHX3	ENST00000397992.5	c.-23-8967T>G		intron_variant		1
ZFHX3	ENST00000641206.2	c.214T>G	p.Ser72Ala	missense_variant	10/18			P1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72249 AN: 151772 Hom.: 18856 Cov.: 32

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.425

GnomAD3 exomes AF: 0.387 AC: 87536 AN: 225974 Hom.: 18540 AF XY: 0.390 AC XY: 48029 AN XY: 123024

Gnomad AFR exome AF: 0.700

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.265

Gnomad SAS exome AF: 0.452

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.395

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.404 AC: 583292 AN: 1444458 Hom.: 121472 Cov.: 80 AF XY: 0.405 AC XY: 290190 AN XY: 716784

Gnomad4 AFR exome AF: 0.713

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.454

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.402

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.476 AC: 72335 AN: 151890 Hom.: 18891 Cov.: 32 AF XY: 0.472 AC XY: 35022 AN XY: 74240

Gnomad4 AFR AF: 0.701

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.457

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.404

Gnomad4 OTH AF: 0.427

Alfa AF: 0.384 Hom.: 10221

Bravo AF: 0.470

TwinsUK AF: 0.396 AC: 1470

ALSPAC AF: 0.407 AC: 1567

ESP6500AA AF: 0.676 AC: 2955

ESP6500EA AF: 0.371 AC: 3183

ExAC AF: 0.365 AC: 43062

Asia WGS AF: 0.397 AC: 1375 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZFHX3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 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	0.051
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.1
Dann	Benign	0.82
DEOGEN2	Benign	0.091	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.029	N
MetaRNN	Benign	0.0000036	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.44	N;.
REVEL	Benign	0.21
Sift	Benign	1.0	T;.
Sift4G	Benign	0.61	T;.
Polyphen		0.0060	B;B
Vest4		0.030
MPC		0.078
ClinPred		0.0057	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.088
gMVP		0.035

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: rs7193297; hg19: chr16-72993831; COSMIC: COSV51707067;