14-23522320-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_033400.3(ZFHX2):​c.7361G>A​(p.Arg2454His) variant causes a missense change. The variant allele was found at a frequency of 0.0000282 in 1,526,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

2
14
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.85
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 39 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZFHX2NM_033400.3 linkuse as main transcriptc.7361G>A p.Arg2454His missense_variant 10/10 ENST00000419474.5 NP_207646.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZFHX2ENST00000419474.5 linkuse as main transcriptc.7361G>A p.Arg2454His missense_variant 10/105 NM_033400.3 ENSP00000413418 P1Q9C0A1-1
ZFHX2-AS1ENST00000553985.1 linkuse as main transcriptn.238+7904C>T intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000554403.1 linkuse as main transcriptn.1068+7904C>T intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000556354.5 linkuse as main transcriptn.465+7904C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000233
AC:
3
AN:
128718
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
69970
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000422
Gnomad ASJ exome
AF:
0.000129
Gnomad EAS exome
AF:
0.0000960
Gnomad SAS 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:
0.0000284
AC:
39
AN:
1374622
Hom.:
0
Cov.:
36
AF XY:
0.0000310
AC XY:
21
AN XY:
677086
show subpopulations
Gnomad4 AFR exome
AF:
0.0000954
Gnomad4 AMR exome
AF:
0.0000286
Gnomad4 ASJ exome
AF:
0.0000406
Gnomad4 EAS exome
AF:
0.000842
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000279
Gnomad4 OTH exome
AF:
0.0000174
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000831
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 29, 2023The c.7361G>A (p.R2454H) alteration is located in exon 10 (coding exon 9) of the ZFHX2 gene. This alteration results from a G to A substitution at nucleotide position 7361, causing the arginine (R) at amino acid position 2454 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.085
T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.87
D
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.53
D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Uncertain
2.1
M
MutationTaster
Benign
0.66
D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-4.0
D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.42
MutPred
0.54
Gain of catalytic residue at R2454 (P = 0.0016);
MVP
0.62
ClinPred
0.94
D
GERP RS
5.0
Varity_R
0.40
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1471234066; hg19: chr14-23991529; API