rs200992486

Variant names:

• chr16-72787445-G-A
• rs200992486
• NM_006885.4:c.10831C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-72787445-G-A
• chr16-72787445-G-C
• chr16-72787445-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006885.4(ZFHX3):​c.10831C>T​(p.His3611Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00786 in 1,604,088 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3611L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 28)
  • Exomes 𝑓: 0.0080 (70 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.07
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062671006).
• BP6: Variant 16-72787445-G-A is Benign according to our data. Variant chr16-72787445-G-A is described in ClinVar as Benign. ClinVar VariationId is 769903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00627 (952/151832) while in subpopulation AMR AF = 0.0132 (202/15274). AF 95% confidence interval is 0.0117. There are 8 homozygotes in GnomAd4. There are 473 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.10831C>T	p.His3611Tyr	missense	Exon 10 of 10	NP_008816.3
	ZFHX3	NM_001386735.1		c.10831C>T	p.His3611Tyr	missense	Exon 17 of 17	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.8089C>T	p.His2697Tyr	missense	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.10831C>T	p.His3611Tyr	missense	Exon 10 of 10	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.8089C>T	p.His2697Tyr	missense	Exon 9 of 9	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.10831C>T	p.His3611Tyr	missense	Exon 18 of 18	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 948 AN: 151720 Hom.: 8 Cov.: 28

Gnomad AFR AF: 0.00281

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00505

Gnomad SAS AF: 0.00606

Gnomad FIN AF: 0.000756

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00791

Gnomad OTH AF: 0.00817

GnomAD2 exomes AF: 0.00724 AC: 1707 AN: 235666 AF XY: 0.00700

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.00148

Gnomad EAS exome AF: 0.00606

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00810

Gnomad OTH exome AF: 0.00713

GnomAD4 exome AF: 0.00803 AC: 11661 AN: 1452256 Hom.: 70 Cov.: 37 AF XY: 0.00788 AC XY: 5681 AN XY: 721234

African (AFR) AF: 0.00243 AC: 81 AN: 33334

American (AMR) AF: 0.0144 AC: 637 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.00155 AC: 40 AN: 25860

East Asian (EAS) AF: 0.00777 AC: 306 AN: 39392

South Asian (SAS) AF: 0.00535 AC: 458 AN: 85630

European-Finnish (FIN) AF: 0.00134 AC: 70 AN: 52350

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5678

European-Non Finnish (NFE) AF: 0.00867 AC: 9589 AN: 1105926

Other (OTH) AF: 0.00787 AC: 472 AN: 59966

GnomAD4 genome AF: 0.00627 AC: 952 AN: 151832 Hom.: 8 Cov.: 28 AF XY: 0.00637 AC XY: 473 AN XY: 74214

African (AFR) AF: 0.00280 AC: 116 AN: 41396

American (AMR) AF: 0.0132 AC: 202 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00507 AC: 26 AN: 5132

South Asian (SAS) AF: 0.00606 AC: 29 AN: 4784

European-Finnish (FIN) AF: 0.000756 AC: 8 AN: 10576

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00791 AC: 537 AN: 67894

Other (OTH) AF: 0.00855 AC: 18 AN: 2106

Alfa AF: 0.00682 Hom.: 9

Bravo AF: 0.00693

ESP6500AA AF: 0.00231 AC: 10

ESP6500EA AF: 0.00601 AC: 51

ExAC AF: 0.00721 AC: 873

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	ZFHX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.043
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.059
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.051	T
Polyphen		0.67	P
Vest4		0.43
MVP		0.043
MPC		0.11
ClinPred		0.096	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.18
Mutation Taster		=79/21	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: rs200992486; hg19: chr16-72821344;