rs10518048

Positions:

• chr16-72946841-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006885.4(ZFHX3):​c.3216+3628C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 152,306 control chromosomes in the GnomAD database, including 79 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 0.026 (79 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.369

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=-0.87).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0257 (3918/152306) while in subpopulation AFR AF= 0.0364 (1514/41568). AF 95% confidence interval is 0.0349. There are 79 homozygotes in gnomad4. There are 1867 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3918 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4	c.3216+3628C>T		intron_variant		ENST00000268489.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10	c.3216+3628C>T		intron_variant		1	NM_006885.4	P1
ZFHX3	ENST00000397992.5	c.474+3628C>T		intron_variant		1
ZFHX3	ENST00000641206.2	c.3216+3628C>T		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3915 AN: 152188 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.0469

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0383

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

GnomAD4 genome AF: 0.0257 AC: 3918 AN: 152306 Hom.: 79 Cov.: 32 AF XY: 0.0251 AC XY: 1867 AN XY: 74474

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.0229

Gnomad4 ASJ AF: 0.0469

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00912

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0235

Gnomad4 OTH AF: 0.0370

Alfa AF: 0.0233 Hom.: 14

Bravo AF: 0.0285

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs10518048; hg19: chr16-72980740;