14-23522131-G-A

Variant summary

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

The NM_033400.3(ZFHX2):​c.7550C>T​(p.Ser2517Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000367 in 1,527,814 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 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79
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)
THTPA (HGNC:18987): (thiamine triphosphatase) This gene encodes an enzyme which catalyzes the biosynthesis of thiamine disphophate (vitamin B1) by hydrolysis of thiamine triphosphate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

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=0.26877594).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZFHX2NM_033400.3 linkuse as main transcriptc.7550C>T p.Ser2517Leu 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.7550C>T p.Ser2517Leu missense_variant 10/105 NM_033400.3 ENSP00000413418 P1Q9C0A1-1
ZFHX2-AS1ENST00000553985.1 linkuse as main transcriptn.238+7715G>A intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000554403.1 linkuse as main transcriptn.1068+7715G>A intron_variant, non_coding_transcript_variant 2
ZFHX2-AS1ENST00000556354.5 linkuse as main transcriptn.465+7715G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.0000400
AC:
5
AN:
124932
Hom.:
0
AF XY:
0.0000295
AC XY:
2
AN XY:
67690
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000857
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000967
Gnomad SAS exome
AF:
0.0000483
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000206
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000371
AC:
51
AN:
1375578
Hom.:
0
Cov.:
36
AF XY:
0.0000339
AC XY:
23
AN XY:
678298
show subpopulations
Gnomad4 AFR exome
AF:
0.000159
Gnomad4 AMR exome
AF:
0.0000864
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000280
Gnomad4 SAS exome
AF:
0.0000386
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000335
Gnomad4 OTH exome
AF:
0.0000174
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152236
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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
Bravo
AF:
0.0000416
ExAC
AF:
0.0000456
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 GeneticsJun 05, 2024The c.7550C>T (p.S2517L) 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 7550, causing the serine (S) at amino acid position 2517 to be replaced by a leucine (L). 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
Uncertain
0.42
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.32
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.061
T
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Benign
0.67
D
LIST_S2
Uncertain
0.87
D
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.27
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-4.1
D
REVEL
Benign
0.11
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.013
D
Polyphen
0.98
D
Vest4
0.49
MutPred
0.27
Gain of catalytic residue at K2522 (P = 6e-04);
MVP
0.54
ClinPred
0.41
T
GERP RS
4.8
Varity_R
0.34
gMVP
0.39

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: rs767636587; hg19: chr14-23991340; COSMIC: COSV104711179; COSMIC: COSV104711179; API