16-72787435-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006885.4(ZFHX3):c.10841G>C(p.Arg3614Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,453,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.924

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09989783).
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4	c.10841G>C	p.Arg3614Thr	missense_variant	10/10	ENST00000268489.10
ZFHX3-AS1	NR_171702.1	n.391-33338C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10	c.10841G>C	p.Arg3614Thr	missense_variant	10/10	1	NM_006885.4	P1
ZFHX3-AS1	ENST00000687589.1	n.482+5616C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 26 AN: 127410 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00114

GnomAD3 exomes AF: 0.0000306 AC: 7 AN: 228950 Hom.: 0 AF XY: 0.0000240 AC XY: 3 AN XY: 125168

Gnomad AFR exome AF: 0.000427

Gnomad AMR exome AF: 0.0000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000981 AC: 13 AN: 1325596 Hom.: 0 Cov.: 35 AF XY: 0.00000913 AC XY: 6 AN XY: 657354

Gnomad4 AFR exome AF: 0.000338

Gnomad4 AMR exome AF: 0.0000505

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000194

GnomAD4 genome AF: 0.000204 AC: 26 AN: 127410 Hom.: 0 Cov.: 27 AF XY: 0.000180 AC XY: 11 AN XY: 61188

Gnomad4 AFR AF: 0.000569

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00114

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.000200

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.10841G>C (p.R3614T) alteration is located in exon 10 (coding exon 9) of the ZFHX3 gene. This alteration results from a G to C substitution at nucleotide position 10841, causing the arginine (R) at amino acid position 3614 to be replaced by a threonine (T). 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	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	23
Dann	Benign	0.92
DEOGEN2	Benign	0.071	T;.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.37	N;N;.
REVEL	Benign	0.16
Sift	Benign	0.18	T;T;.
Sift4G	Benign	0.58	T;T;.
Polyphen		0.12	B;.;B
Vest4		0.20
MVP		0.093
MPC		0.14
ClinPred		0.055	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.41

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: rs760832768; hg19: chr16-72821334;