14-23522119-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_033400.3(ZFHX2):​c.7562G>A​(p.Arg2521His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,531,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.058493435).
BS2
High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZFHX2NM_033400.3 linkuse as main transcriptc.7562G>A p.Arg2521His 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.7562G>A p.Arg2521His missense_variant 10/105 NM_033400.3 ENSP00000413418 P1Q9C0A1-1
ZFHX2-AS1ENST00000553985.1 linkuse as main transcriptn.238+7703C>T intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000554403.1 linkuse as main transcriptn.1068+7703C>T intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000556354.5 linkuse as main transcriptn.465+7703C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000540
AC:
7
AN:
129632
Hom.:
0
AF XY:
0.0000710
AC XY:
5
AN XY:
70396
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000839
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000961
Gnomad SAS exome
AF:
0.000139
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000198
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000188
AC:
26
AN:
1379742
Hom.:
0
Cov.:
36
AF XY:
0.0000294
AC XY:
20
AN XY:
680682
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000569
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000280
Gnomad4 SAS exome
AF:
0.000115
Gnomad4 FIN exome
AF:
0.0000295
Gnomad4 NFE exome
AF:
0.0000121
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152228
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000302

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 GeneticsJan 26, 2023The c.7562G>A (p.R2521H) 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 7562, causing the arginine (R) at amino acid position 2521 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
0.28
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.41
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.00025
T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.042
FATHMM_MKL
Benign
0.50
N
LIST_S2
Uncertain
0.87
D
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.058
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.050
N
MutationTaster
Benign
0.66
D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
0.18
N
REVEL
Benign
0.033
Sift
Benign
0.34
T
Sift4G
Benign
0.52
T
Polyphen
0.12
B
Vest4
0.28
MVP
0.18
ClinPred
0.10
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.063
gMVP
0.18

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1326611029; hg19: chr14-23991328; API