16-72787387-G-A

Position:

• chr16-72787387-G-A

Variant summary

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

The NM_006885.4(ZFHX3):​c.10889C>T​(p.Pro3630Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,180 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: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 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=0.22999144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.10889C>T	p.Pro3630Leu	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.10889C>T	p.Pro3630Leu	missense_variant	10/10	1	NM_006885.4	ENSP00000268489.5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454180 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 722440

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000167

GnomAD4 genome Cov.: 28

Bravo AF: 0.00000378

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

Oct 01, 2024

The c.10889C>T (p.P3630L) alteration is located in exon 10 (coding exon 9) of the ZFHX3 gene. This alteration results from a C to T substitution at nucleotide position 10889, causing the proline (P) at amino acid position 3630 to be replaced by a leucine (L). 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	0.086
BayesDel_addAF	Benign	-0.0026	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T;.;T
Eigen	Benign	-0.063
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	.;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		0.084	B;.;B
Vest4		0.090
MutPred		0.15		Loss of glycosylation at P3630 (P = 0.0098);.;Loss of glycosylation at P3630 (P = 0.0098);
MVP		0.10
MPC		0.095
ClinPred		0.75	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.30

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: rs2035439384; hg19: chr16-72821286;