rs1877354

Positions:

• chr16-73851250-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001386735.1(ZFHX3):​c.-1125+40401T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 151,930 control chromosomes in the GnomAD database, including 10,275 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 0.33 (10275 hom., cov: 32)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.151

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFHX3	NM_001386735.1	c.-1125+40401T>G		intron_variant			NP_001373664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000641206.2	c.-1608+40401T>G		intron_variant				ENSP00000493252	P1
ZFHX3	ENST00000641018.1	n.100+40401T>G		intron_variant, non_coding_transcript_variant
ZFHX3	ENST00000642085.1	n.102+40401T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50635 AN: 151812 Hom.: 10275 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.331

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

GnomAD4 genome AF: 0.333 AC: 50637 AN: 151930 Hom.: 10275 Cov.: 32 AF XY: 0.329 AC XY: 24433 AN XY: 74224

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.434

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.449

Gnomad4 NFE AF: 0.461

Gnomad4 OTH AF: 0.331

Alfa AF: 0.426 Hom.: 19061

Bravo AF: 0.304

Asia WGS AF: 0.263 AC: 916 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1877354; hg19: chr16-73885149;