16-72787404-A-G

Variant names:

• chr16-72787404-A-G
• rs199873559
• NM_006885.4:c.10872T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_006885.4(ZFHX3):​c.10872T>C​(p.Ala3624Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,540,794 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00072 (11 hom.)
• Consequence: ZFHX3 NM_006885.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.81
• Publications: 1 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 16-72787404-A-G is Benign according to our data. Variant chr16-72787404-A-G is described in ClinVar as Benign. ClinVar VariationId is 2646811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000416 (61/146682) while in subpopulation SAS AF = 0.00612 (27/4412). AF 95% confidence interval is 0.00432. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.10872T>C	p.Ala3624Ala	synonymous	Exon 10 of 10	NP_008816.3
	ZFHX3	NM_001386735.1		c.10872T>C	p.Ala3624Ala	synonymous	Exon 17 of 17	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.8130T>C	p.Ala2710Ala	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.10872T>C	p.Ala3624Ala	synonymous	Exon 10 of 10	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.8130T>C	p.Ala2710Ala	synonymous	Exon 9 of 9	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.10872T>C	p.Ala3624Ala	synonymous	Exon 18 of 18	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.000416 AC: 61 AN: 146596 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00449

Gnomad SAS AF: 0.00610

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000600

Gnomad OTH AF: 0.000984

GnomAD2 exomes AF: 0.00108 AC: 260 AN: 241514 AF XY: 0.00127

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.000717 AC: 999 AN: 1394112 Hom.: 11 Cov.: 35 AF XY: 0.000863 AC XY: 598 AN XY: 692976

African (AFR) AF: 0.000417 AC: 13 AN: 31204

American (AMR) AF: 0.0000705 AC: 3 AN: 42566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23386

East Asian (EAS) AF: 0.0105 AC: 358 AN: 34140

South Asian (SAS) AF: 0.00497 AC: 423 AN: 85076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46786

Middle Eastern (MID) AF: 0.000931 AC: 5 AN: 5368

European-Non Finnish (NFE) AF: 0.0000860 AC: 92 AN: 1069860

Other (OTH) AF: 0.00188 AC: 105 AN: 55726

GnomAD4 genome AF: 0.000416 AC: 61 AN: 146682 Hom.: 0 Cov.: 28 AF XY: 0.000574 AC XY: 41 AN XY: 71416

African (AFR) AF: 0.000125 AC: 5 AN: 39932

American (AMR) AF: 0.000134 AC: 2 AN: 14878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00451 AC: 21 AN: 4658

South Asian (SAS) AF: 0.00612 AC: 27 AN: 4412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000600 AC: 4 AN: 66622

Other (OTH) AF: 0.000975 AC: 2 AN: 2052

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000227

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	ZFHX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.8
DANN	Benign	0.85
PhyloP100		1.8
Mutation Taster		=100/0	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: rs199873559; hg19: chr16-72821303; COSMIC: COSV51708485;