14-23522104-G-A

Variant names:

• chr14-23522104-G-A
• rs1041821089
• NM_033400.3:c.7577C>T

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.7577C>T​(p.Pro2526Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,535,282 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: ZFHX2 NM_033400.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• 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=0.11176002).
• BS2: High AC in GnomAdExome4 at 7 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.7577C>T	p.Pro2526Leu	missense	Exon 10 of 10	NP_207646.2	A0A2P1H683
	THTPA	NR_046051.1		n.465+7688G>A		intron	N/A
	THTPA	NR_046052.1		n.245+7688G>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.7577C>T	p.Pro2526Leu	missense	Exon 10 of 10	ENSP00000413418.2	Q9C0A1-1
	ZFHX2-AS1	ENST00000553985.1	TSL:2	n.238+7688G>A		intron	N/A
	ZFHX2-AS1	ENST00000554403.1	TSL:2	n.1068+7688G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000150 AC: 2 AN: 133546 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000506 AC: 7 AN: 1383020 Hom.: 0 Cov.: 36 AF XY: 0.00000147 AC XY: 1 AN XY: 682432

African (AFR) AF: 0.00 AC: 0 AN: 31570

American (AMR) AF: 0.0000281 AC: 1 AN: 35606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25062

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078340

Other (OTH) AF: 0.0000518 AC: 3 AN: 57868

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74390

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000416

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	0.088
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.035	B
Vest4		0.20
MutPred		0.28		Gain of catalytic residue at P2530 (P = 0)
MVP		0.65
ClinPred		0.30	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.11
gMVP		0.33
Mutation Taster		=95/5	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: rs1041821089; hg19: chr14-23991313;