16-72978265-T-C

Variant names:

• chr16-72978265-T-C
• rs11075954
• NM_006885.4:c.-49-18071A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_006885.4(ZFHX3):​c.-49-18071A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 152,030 control chromosomes in the GnomAD database, including 24,735 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 0.56 (24735 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 6 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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Broad Center for Mendelian Genomics
• spinocerebellar ataxia type 4

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.-49-18071A>G		intron_variant	Intron 1 of 9	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10	c.-49-18071A>G		intron_variant	Intron 1 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.-23-27300A>G		intron_variant	Intron 1 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.-49-18071A>G		intron_variant	Intron 9 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85801 AN: 151912 Hom.: 24699 Cov.: 32

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.624

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.570

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

GnomAD4 genome AF: 0.565 AC: 85887 AN: 152030 Hom.: 24735 Cov.: 32 AF XY: 0.572 AC XY: 42488 AN XY: 74326

African (AFR) AF: 0.618 AC: 25658 AN: 41486

American (AMR) AF: 0.614 AC: 9378 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1775 AN: 3466

East Asian (EAS) AF: 0.606 AC: 3129 AN: 5166

South Asian (SAS) AF: 0.505 AC: 2431 AN: 4816

European-Finnish (FIN) AF: 0.624 AC: 6587 AN: 10554

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.518 AC: 35218 AN: 67950

Other (OTH) AF: 0.563 AC: 1190 AN: 2112

Alfa AF: 0.526 Hom.: 35389

Bravo AF: 0.567

Asia WGS AF: 0.553 AC: 1922 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.72
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs11075954; hg19: chr16-73012164;