16-72787446-G-C

Variant names:

• chr16-72787446-G-C
• rs560840757
• NM_006885.4:c.10830C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006885.4(ZFHX3):​c.10830C>G​(p.Pro3610Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,605,262 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00080 (1 hom., cov: 28)
  • Exomes 𝑓: 0.0014 (30 hom.)
• Consequence: ZFHX3 NM_006885.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.173
• Publications: 0 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-AS1 (HGNC:56033): (ZFHX3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 16-72787446-G-C is Benign according to our data. Variant chr16-72787446-G-C is described in ClinVar as Benign. ClinVar VariationId is 3034363.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.173 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000804 (122/151802) while in subpopulation SAS AF = 0.0243 (116/4776). AF 95% confidence interval is 0.0207. There are 1 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006885.4. 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
	ZFHX3	NM_006885.4	MANE Select	c.10830C>G	p.Pro3610Pro	synonymous	Exon 10 of 10	NP_008816.3
	ZFHX3	NM_001386735.1		c.10830C>G	p.Pro3610Pro	synonymous	Exon 17 of 17	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.8088C>G	p.Pro2696Pro	synonymous	Exon 9 of 9	NP_001158238.1	Q15911-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.10830C>G	p.Pro3610Pro	synonymous	Exon 10 of 10	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.8088C>G	p.Pro2696Pro	synonymous	Exon 9 of 9	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.10830C>G	p.Pro3610Pro	synonymous	Exon 18 of 18	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.000804 AC: 122 AN: 151692 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00288 AC: 682 AN: 236416 AF XY: 0.00391

Gnomad AFR exome AF: 0.0000703

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.00137 AC: 1988 AN: 1453460 Hom.: 30 Cov.: 37 AF XY: 0.00199 AC XY: 1438 AN XY: 721876

African (AFR) AF: 0.0000899 AC: 3 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.0221 AC: 1890 AN: 85704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52416

Middle Eastern (MID) AF: 0.000528 AC: 3 AN: 5682

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1106626

Other (OTH) AF: 0.00145 AC: 87 AN: 60008

GnomAD4 genome AF: 0.000804 AC: 122 AN: 151802 Hom.: 1 Cov.: 28 AF XY: 0.00115 AC XY: 85 AN XY: 74216

African (AFR) AF: 0.0000242 AC: 1 AN: 41386

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000584 AC: 3 AN: 5138

South Asian (SAS) AF: 0.0243 AC: 116 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67878

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000170

Asia WGS AF: 0.0100 AC: 35 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ZFHX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.0
DANN	Benign	0.81
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

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: rs560840757; hg19: chr16-72821345; COSMIC: COSV51706648;