chr14-23522332-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_033400.3(ZFHX2):​c.7349G>A​(p.Arg2450His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000783 in 1,532,838 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.73
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.3725767).
BS2
High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZFHX2NM_033400.3 linkuse as main transcriptc.7349G>A p.Arg2450His 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.7349G>A p.Arg2450His missense_variant 10/105 NM_033400.3 ENSP00000413418 P1Q9C0A1-1
ZFHX2-AS1ENST00000553985.1 linkuse as main transcriptn.238+7916C>T intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000554403.1 linkuse as main transcriptn.1068+7916C>T intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000556354.5 linkuse as main transcriptn.465+7916C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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
GnomAD3 exomes
AF:
0.0000152
AC:
2
AN:
131838
Hom.:
0
AF XY:
0.0000139
AC XY:
1
AN XY:
71702
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000454
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000194
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000724
AC:
10
AN:
1380600
Hom.:
0
Cov.:
36
AF XY:
0.00000587
AC XY:
4
AN XY:
680918
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000254
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000743
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152238
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000113

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 10, 2023The c.7349G>A (p.R2450H) 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 7349, causing the arginine (R) at amino acid position 2450 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
0.14
BayesDel_addAF
Benign
-0.031
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.011
T
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.77
T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.37
T
MetaSVM
Benign
-0.36
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.5
N
REVEL
Uncertain
0.46
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.040
D
Polyphen
1.0
D
Vest4
0.36
MutPred
0.45
Gain of catalytic residue at T2448 (P = 4e-04);
MVP
0.51
ClinPred
0.70
D
GERP RS
5.0
Varity_R
0.13
gMVP
0.33

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: rs1004004426; hg19: chr14-23991541; API