14-23522254-A-G

Variant names:

• chr14-23522254-A-G
• rs561588842
• NM_033400.3:c.7427T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033400.3(ZFHX2):​c.7427T>C​(p.Phe2476Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. F2476Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZFHX2 NM_033400.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.7427T>C	p.Phe2476Ser	missense	Exon 10 of 10	NP_207646.2	A0A2P1H683
	THTPA	NR_046051.1		n.465+7838A>G		intron	N/A
	THTPA	NR_046052.1		n.245+7838A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX2	ENST00000419474.5	TSL:5 MANE Select	c.7427T>C	p.Phe2476Ser	missense	Exon 10 of 10	ENSP00000413418.2	Q9C0A1-1
	ZFHX2-AS1	ENST00000553985.1	TSL:2	n.238+7838A>G		intron	N/A
	ZFHX2-AS1	ENST00000554403.1	TSL:2	n.1068+7838A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.70
MutPred		0.63		Gain of catalytic residue at F2476 (P = 0)
MVP		0.53
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.53
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: rs561588842; hg19: chr14-23991463;