chr16-72787228-T-G

Variant names:

• chr16-72787228-T-G
• rs1256180973
• NM_006885.4:c.11048A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006885.4(ZFHX3):​c.11048A>C​(p.Lys3683Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K3683R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.097240955).

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.11048A>C	p.Lys3683Thr	missense	Exon 10 of 10	NP_008816.3
	ZFHX3	NM_001386735.1		c.11048A>C	p.Lys3683Thr	missense	Exon 17 of 17	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.8306A>C	p.Lys2769Thr	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.11048A>C	p.Lys3683Thr	missense	Exon 10 of 10	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.8306A>C	p.Lys2769Thr	missense	Exon 9 of 9	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.11048A>C	p.Lys3683Thr	missense	Exon 18 of 18	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251462 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 29

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	0.12
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.20
Sift	Benign	0.035	D
Sift4G	Benign	0.30	T
Polyphen		0.037	B
Vest4		0.22
MutPred		0.21		Loss of ubiquitination at K3683 (P = 4e-04)
MVP		0.043
MPC		0.11
ClinPred		0.18	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.17

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: rs1256180973; hg19: chr16-72821127;