16-72787387-G-A

Variant names:

• chr16-72787387-G-A
• rs2035439384
• NM_006885.4:c.10889C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22999144).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006885.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_006885.4	MANE Select	c.10889C>T	p.Pro3630Leu	missense	Exon 10 of 10	NP_008816.3
	ZFHX3	NM_001386735.1		c.10889C>T	p.Pro3630Leu	missense	Exon 17 of 17	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.8147C>T	p.Pro2716Leu	missense	Exon 9 of 9	NP_001158238.1	Q15911-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.10889C>T	p.Pro3630Leu	missense	Exon 10 of 10	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.8147C>T	p.Pro2716Leu	missense	Exon 9 of 9	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.10889C>T	p.Pro3630Leu	missense	Exon 18 of 18	ENSP00000493252.1	Q15911-1

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

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 85824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106296

Other (OTH) AF: 0.0000167 AC: 1 AN: 59994

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.063
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.084	B
Vest4		0.090
MutPred		0.15		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
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs2035439384; hg19: chr16-72821286;