NM_006885.4:c.10975G>C

Variant names:

• chr16-72787301-C-G
• rs1374726770
• NM_006885.4:c.10975G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006885.4(ZFHX3):​c.10975G>C​(p.Asp3659His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17787945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.10975G>C	p.Asp3659His	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.10975G>C	p.Asp3659His	missense_variant	Exon 10 of 10	1	NM_006885.4	ENSP00000268489.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.1	L;.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.99	N;N;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.011	D;D;.
Sift4G	Uncertain	0.018	D;D;.
Polyphen		0.85	P;.;P
Vest4		0.34
MutPred		0.063		Loss of phosphorylation at T3657 (P = 0.12);.;Loss of phosphorylation at T3657 (P = 0.12);
MVP		0.12
MPC		0.11
ClinPred		0.27	T
GERP RS		3.8
Varity_R		0.14
gMVP		0.20

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: rs1374726770; hg19: chr16-72821200;