NM_033400.3:c.7427T>A

Variant names:

• chr14-23522254-A-T
• rs561588842
• NM_033400.3:c.7427T>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.7427T>A​(p.Phe2476Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,482,006 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. F2476S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11442384).
• BS2: High AC in GnomAd4 at 31 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.7427T>A	p.Phe2476Tyr	missense	Exon 10 of 10	NP_207646.2	A0A2P1H683
	THTPA	NR_046051.1		n.465+7838A>T		intron	N/A
	THTPA	NR_046052.1		n.245+7838A>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.7427T>A	p.Phe2476Tyr	missense	Exon 10 of 10	ENSP00000413418.2	Q9C0A1-1
	ZFHX2-AS1	ENST00000553985.1	TSL:2	n.238+7838A>T		intron	N/A
	ZFHX2-AS1	ENST00000554403.1	TSL:2	n.1068+7838A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000699

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: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.0000541 AC: 5 AN: 92360 AF XY: 0.0000207

Gnomad AFR exome AF: 0.000830

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: 0.0000173 AC: 23 AN: 1329640 Hom.: 0 Cov.: 36 AF XY: 0.0000139 AC XY: 9 AN XY: 649196

African (AFR) AF: 0.000562 AC: 17 AN: 30254

American (AMR) AF: 0.0000666 AC: 2 AN: 30016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21264

East Asian (EAS) AF: 0.00 AC: 0 AN: 35278

South Asian (SAS) AF: 0.00 AC: 0 AN: 70142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5362

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050172

Other (OTH) AF: 0.0000721 AC: 4 AN: 55460

GnomAD4 genome AF: 0.000203 AC: 31 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13 AN XY: 74512

African (AFR) AF: 0.000697 AC: 29 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000212

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	0.27
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.44		Gain of catalytic residue at S2480 (P = 0)
MVP		0.21
ClinPred		0.20	T
GERP RS		5.0
Varity_R		0.53
gMVP		0.24
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;