16-72787694-AGCCGCCGCC-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BS1 BS2

The NM_006885.4(ZFHX3):c.10573_10581del(p.Gly3525_Gly3527del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0329 in 1,420,694 control chromosomes in the GnomAD database, including 3,693 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (44 hom., cov: 29)
  • Exomes 𝑓: 0.034 (3649 hom.)
• Consequence: ZFHX3 NM_006885.4 inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.41

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 Benign. Variant got -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006885.4
• BP6: Variant 16-72787694-AGCCGCCGCC-A is Benign according to our data. Variant chr16-72787694-AGCCGCCGCC-A is described in ClinVar as [Benign]. Clinvar id is 3058928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-72787694-AGCCGCCGCC-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0211 (3132/148526) while in subpopulation NFE AF= 0.0276 (1848/66906). AF 95% confidence interval is 0.0266. There are 44 homozygotes in gnomad4. There are 1506 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd at 3132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4	c.10573_10581del	p.Gly3525_Gly3527del	inframe_deletion	10/10	ENST00000268489.10
ZFHX3-AS1	NR_171702.1	n.391-33063_391-33055del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10	c.10573_10581del	p.Gly3525_Gly3527del	inframe_deletion	10/10	1	NM_006885.4	P1
ZFHX3-AS1	ENST00000687589.1	n.482+5891_482+5899del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3132 AN: 148424 Hom.: 44 Cov.: 29

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0108

Gnomad EAS AF: 0.00581

Gnomad SAS AF: 0.0185

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0290

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0202

GnomAD4 exome AF: 0.0343 AC: 43600 AN: 1272168 Hom.: 3649 AF XY: 0.0347 AC XY: 21678 AN XY: 625152

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.0219

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.00594

Gnomad4 SAS exome AF: 0.0490

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0356

Gnomad4 OTH exome AF: 0.0311

GnomAD4 genome AF: 0.0211 AC: 3132 AN: 148526 Hom.: 44 Cov.: 29 AF XY: 0.0208 AC XY: 1506 AN XY: 72350

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0108

Gnomad4 EAS AF: 0.00583

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.0303

Gnomad4 NFE AF: 0.0276

Gnomad4 OTH AF: 0.0200

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZFHX3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs374416547; hg19: chr16-72821593;