chr14-23522137-C-T

Variant names:

• chr14-23522137-C-T
• rs111511226
• NM_033400.3:c.7544G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033400.3(ZFHX2):​c.7544G>A​(p.Arg2515His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000715 in 1,525,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2515C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: ZFHX2 NM_033400.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03
• Publications: 0 publications found

Genes affected

ZFHX2 (HGNC:20152): (zinc finger homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in regulation of sensory perception of pain. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZFHX2-AS1 (HGNC:52658): (ZFHX2 antisense RNA 1)

THTPA (HGNC:18987): (thiamine triphosphatase) This gene encodes an enzyme which catalyzes the biosynthesis of thiamine disphophate (vitamin B1) by hydrolysis of thiamine triphosphate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15792099).
• BS2: High AC in GnomAd4 at 28 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033400.3. 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
	ZFHX2	NM_033400.3	MANE Select	c.7544G>A	p.Arg2515His	missense	Exon 10 of 10	NP_207646.2	A0A2P1H683
	THTPA	NR_046051.1		n.465+7721C>T		intron	N/A
	THTPA	NR_046052.1		n.245+7721C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX2	ENST00000419474.5	TSL:5 MANE Select	c.7544G>A	p.Arg2515His	missense	Exon 10 of 10	ENSP00000413418.2	Q9C0A1-1
	ZFHX2-AS1	ENST00000553985.1	TSL:2	n.238+7721C>T		intron	N/A
	ZFHX2-AS1	ENST00000554403.1	TSL:2	n.1068+7721C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000490 AC: 6 AN: 122448 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000433

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000226

Gnomad NFE exome AF: 0.0000843

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000590 AC: 81 AN: 1372972 Hom.: 0 Cov.: 36 AF XY: 0.0000606 AC XY: 41 AN XY: 676810

African (AFR) AF: 0.00 AC: 0 AN: 31320

American (AMR) AF: 0.0000290 AC: 1 AN: 34506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35702

South Asian (SAS) AF: 0.00 AC: 0 AN: 77358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.0000736 AC: 79 AN: 1073436

Other (OTH) AF: 0.0000174 AC: 1 AN: 57406

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000945 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000459 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0081	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.28
MutPred		0.24		Loss of MoRF binding (P = 0.0107)
MVP		0.30
ClinPred		0.18	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.23
gMVP		0.15
Mutation Taster		=91/9	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: rs111511226; hg19: chr14-23991346;