16-72787694-A-AGCC

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_006885.4(ZFHX3):c.10581_10582insGGC(p.Gly3527dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0304 in 1,416,790 control chromosomes in the GnomAD database, including 546 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (144 hom., cov: 29)
  • Exomes 𝑓: 0.029 (402 hom.)
• Consequence: ZFHX3 NM_006885.4 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.01

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-A-AGCC is Benign according to our data. Variant chr16-72787694-A-AGCC is described in ClinVar as [Benign]. Clinvar id is 3056720.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4	c.10581_10582insGGC	p.Gly3527dup	inframe_insertion	10/10	ENST00000268489.10
ZFHX3-AS1	NR_171702.1	n.391-33057_391-33055dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10	c.10581_10582insGGC	p.Gly3527dup	inframe_insertion	10/10	1	NM_006885.4	P1
ZFHX3-AS1	ENST00000687589.1	n.482+5897_482+5899dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 5958 AN: 148402 Hom.: 143 Cov.: 29

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.0683

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.0903

Gnomad NFE AF: 0.0368

Gnomad OTH AF: 0.0433

GnomAD4 exome AF: 0.0292 AC: 37076 AN: 1268286 Hom.: 402 Cov.: 35 AF XY: 0.0292 AC XY: 18202 AN XY: 623170

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.00941

Gnomad4 ASJ exome AF: 0.0316

Gnomad4 EAS exome AF: 0.00193

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0181

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0303

GnomAD4 genome AF: 0.0402 AC: 5976 AN: 148504 Hom.: 144 Cov.: 29 AF XY: 0.0384 AC XY: 2780 AN XY: 72346

Gnomad4 AFR AF: 0.0588

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.0406

Gnomad4 EAS AF: 0.00520

Gnomad4 SAS AF: 0.0258

Gnomad4 FIN AF: 0.0269

Gnomad4 NFE AF: 0.0368

Gnomad4 OTH AF: 0.0428

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

Jun 27, 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;