16-72995261-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006885.4(ZFHX3):c.-49-35067A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 152,012 control chromosomes in the GnomAD database, including 46,978 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (46978 hom., cov: 31)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.484

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4	c.-49-35067A>G		intron_variant		ENST00000268489.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10	c.-49-35067A>G		intron_variant		1	NM_006885.4	P1
ZFHX3	ENST00000397992.5	c.-23-44296A>G		intron_variant		1
ZFHX3	ENST00000641206.2	c.-49-35067A>G		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118515 AN: 151896 Hom.: 46944 Cov.: 31

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.809

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.780 AC: 118603 AN: 152012 Hom.: 46978 Cov.: 31 AF XY: 0.770 AC XY: 57203 AN XY: 74264

Gnomad4 AFR AF: 0.762

Gnomad4 AMR AF: 0.778

Gnomad4 ASJ AF: 0.861

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.676

Gnomad4 FIN AF: 0.748

Gnomad4 NFE AF: 0.830

Gnomad4 OTH AF: 0.810

Alfa AF: 0.818 Hom.: 119871

Bravo AF: 0.782

Asia WGS AF: 0.570 AC: 1982 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.31
Dann	Benign	0.71

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: rs7193343; hg19: chr16-73029160;