14-23522288-G-A

Variant names:

• chr14-23522288-G-A
• rs1177092725
• NM_033400.3:c.7393C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_033400.3(ZFHX2):​c.7393C>T​(p.Pro2465Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000887 in 1,352,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P2465L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ZFHX2 NM_033400.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05412659).
• BS2: High AC in GnomAdExome4 at 12 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.7393C>T	p.Pro2465Ser	missense	Exon 10 of 10	NP_207646.2	A0A2P1H683
	THTPA	NR_046051.1		n.465+7872G>A		intron	N/A
	THTPA	NR_046052.1		n.245+7872G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX2	ENST00000419474.5	TSL:5 MANE Select	c.7393C>T	p.Pro2465Ser	missense	Exon 10 of 10	ENSP00000413418.2	Q9C0A1-1
	ZFHX2-AS1	ENST00000553985.1	TSL:2	n.238+7872G>A		intron	N/A
	ZFHX2-AS1	ENST00000554403.1	TSL:2	n.1068+7872G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 112664 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000887 AC: 12 AN: 1352710 Hom.: 0 Cov.: 35 AF XY: 0.00000151 AC XY: 1 AN XY: 663260

African (AFR) AF: 0.00 AC: 0 AN: 31066

American (AMR) AF: 0.00 AC: 0 AN: 33266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23016

East Asian (EAS) AF: 0.00 AC: 0 AN: 35410

South Asian (SAS) AF: 0.00 AC: 0 AN: 74302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 0.0000113 AC: 12 AN: 1060894

Other (OTH) AF: 0.00 AC: 0 AN: 56474

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	0.093
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.00029	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.14
Sift	Benign	0.22	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.26		Gain of catalytic residue at H2469 (P = 0.0032)
MVP		0.25
ClinPred		0.26	T
GERP RS		4.1
Varity_R		0.040
gMVP		0.17
Mutation Taster		=97/3	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: rs1177092725; hg19: chr14-23991497;