Variant chr14-23521990-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_033400.3(ZFHX2):c.7691C>T(p.Thr2564Met) variant causes a missense change. The variant allele was found at a frequency of 0.000139 in 1,536,404 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 0.00013 ( 1 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47

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:):

THTPA links:

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=0.15207839).

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFHX2	NM_033400.3 linkuse as main transcript	c.7691C>T	p.Thr2564Met	missense_variant	10/10	ENST00000419474.5	NP_207646.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFHX2	ENST00000419474.5 linkuse as main transcript	c.7691C>T	p.Thr2564Met	missense_variant	10/10	5	NM_033400.3	ENSP00000413418	P1	Q9C0A1-1
ZFHX2-AS1	ENST00000553985.1 linkuse as main transcript	n.238+7574G>A		intron_variant, non_coding_transcript_variant		2
ZFHX2-AS1	ENST00000554403.1 linkuse as main transcript	n.1068+7574G>A		intron_variant, non_coding_transcript_variant		2
ZFHX2-AS1	ENST00000556354.5 linkuse as main transcript	n.465+7574G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000132

AC:

AN:

136294

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

74076

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000578

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000746

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

183

AN:

1384044

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

103

AN XY:

682972

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.000196

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000112

Gnomad4 SAS exome

AF:

0.000517

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000109

Gnomad4 OTH exome

AF:

0.000207

GnomAD4 genome

AF:

0.000203

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000206

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000315

AC:

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 submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.7691C>T (p.T2564M) 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 7691, causing the threonine (T) at amino acid position 2564 to be replaced by a methionine (M). 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

0.20

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.15

MetaSVM

Uncertain

0.00060

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.43

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.022

Polyphen

1.0

Vest4

0.38

MutPred

0.20

Gain of catalytic residue at S2567 (P = 0.002);

MVP

0.57

ClinPred

0.12

GERP RS

4.8

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.

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