rs1268697084

Variant names:

• chr16-72787369-G-A
• rs1268697084
• NM_006885.4:c.10907C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-72787369-G-A
• chr16-72787369-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006885.4(ZFHX3):​c.10907C>T​(p.Ser3636Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.85

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.10907C>T	p.Ser3636Phe	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.10907C>T	p.Ser3636Phe	missense_variant	Exon 10 of 10	1	NM_006885.4	ENSP00000268489.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457890 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10907C>T (p.S3636F) 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 10907, causing the serine (S) at amino acid position 3636 to be replaced by a phenylalanine (F). 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	0.33
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T;.;T
Eigen	Benign	0.064
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M;.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.014	B;.;B
Vest4		0.45
MVP		0.068
MPC		0.10
ClinPred		0.97	D
GERP RS		3.6
Varity_R		0.68
gMVP		0.43

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: rs1268697084; hg19: chr16-72821268;