NM_006885.4:c.10832A>C

Variant names:

• chr16-72787444-T-G
• rs1385611265
• NM_006885.4:c.10832A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006885.4(ZFHX3):​c.10832A>C​(p.His3611Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3611Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00060 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1650252).

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.10832A>C	p.His3611Pro	missense	Exon 10 of 10	NP_008816.3
	ZFHX3	NM_001386735.1		c.10832A>C	p.His3611Pro	missense	Exon 17 of 17	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.8090A>C	p.His2697Pro	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.10832A>C	p.His3611Pro	missense	Exon 10 of 10	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.8090A>C	p.His2697Pro	missense	Exon 9 of 9	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.10832A>C	p.His3611Pro	missense	Exon 18 of 18	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 60 AN: 17648 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00285

Gnomad SAS AF: 0.00154

Gnomad FIN AF: 0.00606

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000212 AC: 38 AN: 179316 AF XY: 0.000250

Gnomad AFR exome AF: 0.000205

Gnomad AMR exome AF: 0.000224

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000491

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.000515

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000601 AC: 625 AN: 1040404 Hom.: 0 Cov.: 36 AF XY: 0.000653 AC XY: 329 AN XY: 503934

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000574 AC: 13 AN: 22632

American (AMR) AF: 0.00121 AC: 33 AN: 27282

Ashkenazi Jewish (ASJ) AF: 0.000511 AC: 7 AN: 13690

East Asian (EAS) AF: 0.00145 AC: 18 AN: 12440

South Asian (SAS) AF: 0.00249 AC: 117 AN: 46894

European-Finnish (FIN) AF: 0.00138 AC: 31 AN: 22532

Middle Eastern (MID) AF: 0.000539 AC: 2 AN: 3710

European-Non Finnish (NFE) AF: 0.000431 AC: 368 AN: 854696

Other (OTH) AF: 0.000986 AC: 36 AN: 36528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00339 AC: 60 AN: 17690 Hom.: 0 Cov.: 0 AF XY: 0.00245 AC XY: 23 AN XY: 9382

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00360 AC: 16 AN: 4448

American (AMR) AF: 0.00334 AC: 7 AN: 2098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 406

East Asian (EAS) AF: 0.00287 AC: 2 AN: 696

South Asian (SAS) AF: 0.00153 AC: 1 AN: 652

European-Finnish (FIN) AF: 0.00606 AC: 6 AN: 990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 60

European-Non Finnish (NFE) AF: 0.00353 AC: 28 AN: 7940

Other (OTH) AF: 0.00 AC: 0 AN: 334

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00298 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.17	T
Polyphen		0.88	P
Vest4		0.38
MutPred		0.23		Gain of glycosylation at H3611 (P = 0.003)
MVP		0.043
MPC		0.15
ClinPred		0.13	T
GERP RS		3.0
Varity_R		0.43
gMVP		0.24
Mutation Taster		=58/42	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: rs1385611265; hg19: chr16-72821343;