16-72787423-G-A

Variant names:

• chr16-72787423-G-A
• rs202087317
• NM_006885.4:c.10853C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_006885.4(ZFHX3):​c.10853C>T​(p.Pro3618Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000605 in 1,602,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P3618P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.71

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000613 (89/1451166) while in subpopulation MID AF= 0.000525 (3/5714). AF 95% confidence interval is 0.000222. There are 0 homozygotes in gnomad4_exome. There are 52 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.10853C>T	p.Pro3618Leu	missense_variant	Exon 10 of 10	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10	c.10853C>T	p.Pro3618Leu	missense_variant	Exon 10 of 10	1	NM_006885.4	ENSP00000268489.5

Frequencies

GnomAD3 genomes AF: 0.0000530 AC: 8 AN: 151076 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000621 AC: 15 AN: 241694 Hom.: 0 AF XY: 0.0000836 AC XY: 11 AN XY: 131574

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000302

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000460

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000613 AC: 89 AN: 1451166 Hom.: 0 Cov.: 35 AF XY: 0.0000722 AC XY: 52 AN XY: 720546

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000316

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000462

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.0000530 AC: 8 AN: 151076 Hom.: 0 Cov.: 28 AF XY: 0.0000542 AC XY: 4 AN XY: 73760

Gnomad4 AFR AF: 0.0000487

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000591

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000582 Hom.: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10853C>T (p.P3618L) alteration is located in exon 10 (coding exon 9) of the ZFHX3 gene. This alteration results from a C to T substitution at nucleotide position 10853, causing the proline (P) at amino acid position 3618 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.37	T;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	.;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.0	M;.;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.0	D;D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		0.98	D;.;D
Vest4		0.34
MVP		0.23
MPC		0.095
ClinPred		0.57	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs202087317; hg19: chr16-72821322;