Genetic Variant ZFHX2:p.Arg2521His (chr14-23522119-C-T) – ACMG Classification: Benign (-8 pts)

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

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 links:

ZFHX2-AS1 (HGNC:52658): (ZFHX2 antisense RNA 1)

ZFHX2-AS1 links:

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]

THTPA links:

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 rank	MANE	Protein	UniProt
ZFHX2	NM_033400.3 link	c.7562G>A	p.Arg2521His	missense_variant	Exon 10 of 10	ENST00000419474.5	NP_207646.2	Q9C0A1-1B7ZM83A0A2P1H683B9EK48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZFHX2	ENST00000419474.5 link	c.7562G>A	p.Arg2521His	missense_variant	Exon 10 of 10	5	NM_033400.3	ENSP00000413418.2	Q9C0A1-1
ZFHX2-AS1	ENST00000553985.1 link	n.238+7703C>T		intron_variant	Intron 2 of 2	2
ZFHX2-AS1	ENST00000554403.1 link	n.1068+7703C>T		intron_variant	Intron 1 of 2	2
ZFHX2-AS1	ENST00000556354.5 link	n.465+7703C>T		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152228

Hom.:

Cov.:

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:

AN:

129632

Hom.:

AF XY:

0.0000710

AC XY:

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:

AN:

1379742

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

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:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

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.:

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

Jan 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.00025

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.042

FATHMM_MKL

Benign

0.50

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0041

MetaRNN

Benign

0.058

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.050

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.18

REVEL

Benign

0.033

Sift

Benign

0.34

Sift4G

Benign

0.52

Polyphen

0.12

Vest4

0.28

MVP

0.18

ClinPred

0.10

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over