16-72787224-G-C

Position:

• chr16-72787224-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000268489.10(ZFHX3):​c.11052C>G​(p.Asp3684Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: ZFHX3 ENST00000268489.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09911686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.11052C>G	p.Asp3684Glu	missense_variant	10/10	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10	c.11052C>G	p.Asp3684Glu	missense_variant	10/10	1	NM_006885.4	ENSP00000268489.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 29

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

Mar 30, 2024

The c.11052C>G (p.D3684E) alteration is located in exon 10 (coding exon 9) of the ZFHX3 gene. This alteration results from a C to G substitution at nucleotide position 11052, causing the aspartic acid (D) at amino acid position 3684 to be replaced by a glutamic acid (E). 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	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.068	T;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.083
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.57	.;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	0.89	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.68	N;N;.
REVEL	Benign	0.13
Sift	Benign	0.11	T;T;.
Sift4G	Benign	0.39	T;T;.
Polyphen		0.0	B;.;B
Vest4		0.078
MutPred		0.080		Gain of catalytic residue at D3684 (P = 0.1338);.;Gain of catalytic residue at D3684 (P = 0.1338);
MVP		0.082
MPC		0.087
ClinPred		0.41	T
GERP RS		5.5
Varity_R		0.078
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-72821123;