8-76699390-A-G

Variant names:

• chr8-76699390-A-G
• rs4735738
• NM_024721.5:c.-46-4653A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024721.5(ZFHX4):​c.-46-4653A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 151,890 control chromosomes in the GnomAD database, including 11,614 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 0.32 (11614 hom., cov: 32)
• Consequence: ZFHX4 NM_024721.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 9 publications found

Genes affected

ZFHX4 (HGNC:30939): (zinc finger homeobox 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZFHX4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, Broad Center for Mendelian Genomics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ptosis, hereditary congenital, 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024721.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX4	NM_024721.5	MANE Select	c.-46-4653A>G		intron	N/A	NP_078997.4
	ZFHX4	NM_001410934.1		c.-46-4653A>G		intron	N/A	NP_001397863.1	E7EVZ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX4	ENST00000651372.2	MANE Select	c.-46-4653A>G		intron	N/A	ENSP00000498627.1	Q86UP3-5
	ZFHX4	ENST00000523885.2	TSL:4	c.-46-4653A>G		intron	N/A	ENSP00000429495.2	E5RI93
	ZFHX4	ENST00000517585.1	TSL:4	c.-46-4653A>G		intron	N/A	ENSP00000427775.1	E5RG79

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48615 AN: 151772 Hom.: 11574 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.321 AC: 48704 AN: 151890 Hom.: 11614 Cov.: 32 AF XY: 0.318 AC XY: 23625 AN XY: 74246

African (AFR) AF: 0.668 AC: 27652 AN: 41384

American (AMR) AF: 0.225 AC: 3437 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 449 AN: 3466

East Asian (EAS) AF: 0.451 AC: 2321 AN: 5146

South Asian (SAS) AF: 0.221 AC: 1065 AN: 4816

European-Finnish (FIN) AF: 0.199 AC: 2100 AN: 10562

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10974 AN: 67940

Other (OTH) AF: 0.270 AC: 570 AN: 2110

Alfa AF: 0.240 Hom.: 11355

Bravo AF: 0.338

Asia WGS AF: 0.317 AC: 1102 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	7.8
DANN	Benign	0.46
PhyloP100		2.1
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: rs4735738; hg19: chr8-77611625;