chr14-23522249-G-A

Variant summary

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

The NM_033400.3(ZFHX2):​c.7432C>T​(p.Arg2478Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,480,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00400
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 GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZFHX2NM_033400.3 linkuse as main transcriptc.7432C>T p.Arg2478Trp 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.7432C>T p.Arg2478Trp missense_variant 10/105 NM_033400.3 ENSP00000413418 P1Q9C0A1-1
ZFHX2-AS1ENST00000553985.1 linkuse as main transcriptn.238+7833G>A intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000554403.1 linkuse as main transcriptn.1068+7833G>A intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000556354.5 linkuse as main transcriptn.465+7833G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152246
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000723
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000392
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000209
AC:
19
AN:
90860
Hom.:
0
AF XY:
0.000339
AC XY:
16
AN XY:
47260
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000106
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000320
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000377
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000214
AC:
284
AN:
1327942
Hom.:
0
Cov.:
36
AF XY:
0.000252
AC XY:
163
AN XY:
648040
show subpopulations
Gnomad4 AFR exome
AF:
0.000132
Gnomad4 AMR exome
AF:
0.000200
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000284
Gnomad4 SAS exome
AF:
0.000244
Gnomad4 FIN exome
AF:
0.0000632
Gnomad4 NFE exome
AF:
0.000230
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152246
Hom.:
0
Cov.:
33
AF XY:
0.000175
AC XY:
13
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000131
Hom.:
0
Bravo
AF:
0.000196
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

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 GeneticsMay 04, 2022The c.7432C>T (p.R2478W) alteration is located in exon 10 (coding exon 9) of the ZFHX2 gene. This alteration results from a C to T substitution at nucleotide position 7432, causing the arginine (R) at amino acid position 2478 to be replaced by a tryptophan (W). 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
0.24
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.046
T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.046
D
MetaRNN
Uncertain
0.53
D
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
0.51
D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-3.2
D
REVEL
Benign
0.27
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.55
MutPred
0.43
Gain of catalytic residue at S2480 (P = 0);
MVP
0.48
ClinPred
0.19
T
GERP RS
4.0
Varity_R
0.29
gMVP
0.20

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: rs753985089; hg19: chr14-23991458; API