14-23522254-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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 (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.57
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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11442384).
BS2
High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZFHX2NM_033400.3 linkuse as main transcriptc.7427T>A p.Phe2476Tyr 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.7427T>A p.Phe2476Tyr missense_variant 10/105 NM_033400.3 ENSP00000413418 P1Q9C0A1-1
ZFHX2-AS1ENST00000553985.1 linkuse as main transcriptn.238+7838A>T intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000554403.1 linkuse as main transcriptn.1068+7838A>T intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000556354.5 linkuse as main transcriptn.465+7838A>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.0000541
AC:
5
AN:
92360
Hom.:
0
AF XY:
0.0000207
AC XY:
1
AN XY:
48342
show subpopulations
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 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:
0.0000173
AC:
23
AN:
1329640
Hom.:
0
Cov.:
36
AF XY:
0.0000139
AC XY:
9
AN XY:
649196
show subpopulations
Gnomad4 AFR exome
AF:
0.000562
Gnomad4 AMR exome
AF:
0.0000666
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000721
GnomAD4 genome
AF:
0.000203
AC:
31
AN:
152366
Hom.:
0
Cov.:
33
AF XY:
0.000174
AC XY:
13
AN XY:
74512
show subpopulations
Gnomad4 AFR
AF:
0.000697
Gnomad4 AMR
AF:
0.00
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:
0.000946
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000212

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 GeneticsJul 06, 2021The c.7427T>A (p.F2476Y) alteration is located in exon 10 (coding exon 9) of the ZFHX2 gene. This alteration results from a T to A substitution at nucleotide position 7427, causing the phenylalanine (F) at amino acid position 2476 to be replaced by a tyrosine (Y). 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
0.27
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
MutationTaster
Benign
1.0
D;N
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

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: rs561588842; hg19: chr14-23991463; API