16-72787694-AGCCGCC-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_006885.4(ZFHX3):c.10576_10581del(p.Gly3526_Gly3527del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00182 in 1,420,704 control chromosomes in the GnomAD database, including 94 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 29)
  • Exomes 𝑓: 0.0017 (90 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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006885.4
• BP6: Variant 16-72787694-AGCCGCC-A is Benign according to our data. Variant chr16-72787694-AGCCGCC-A is described in ClinVar as [Benign]. Clinvar id is 3034404.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-72787694-AGCCGCC-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 405 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4	c.10576_10581del	p.Gly3526_Gly3527del	inframe_deletion	10/10	ENST00000268489.10
ZFHX3-AS1	NR_171702.1	n.391-33060_391-33055del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10	c.10576_10581del	p.Gly3526_Gly3527del	inframe_deletion	10/10	1	NM_006885.4	P1
ZFHX3-AS1	ENST00000687589.1	n.482+5894_482+5899del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 405 AN: 148442 Hom.: 5 Cov.: 29

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00905

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.000202

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000777

Gnomad OTH AF: 0.00394

GnomAD4 exome AF: 0.00171 AC: 2178 AN: 1272160 Hom.: 90 AF XY: 0.00185 AC XY: 1154 AN XY: 625134

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00966

Gnomad4 ASJ exome AF: 0.0000950

Gnomad4 EAS exome AF: 0.0123

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.000117

Gnomad4 NFE exome AF: 0.000674

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00273 AC: 406 AN: 148544 Hom.: 4 Cov.: 29 AF XY: 0.00332 AC XY: 240 AN XY: 72358

Gnomad4 AFR AF: 0.00235

Gnomad4 AMR AF: 0.00924

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.0121

Gnomad4 FIN AF: 0.000202

Gnomad4 NFE AF: 0.000777

Gnomad4 OTH AF: 0.00438

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

Sep 10, 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;