dbSNP rs766572697: ZFHX2:p.Gly2482Val (chr14-23522236-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

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

The NM_033400.3(ZFHX2):c.7445G>T(p.Gly2482Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,322,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2482D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.634

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11196202).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX2	NM_033400.3 link	c.7445G>T	p.Gly2482Val	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.7445G>T	p.Gly2482Val	missense_variant	Exon 10 of 10	5	NM_033400.3	ENSP00000413418.2	Q9C0A1-1
ZFHX2-AS1	ENST00000553985.1 link	n.238+7820C>A		intron_variant	Intron 2 of 2	2
ZFHX2-AS1	ENST00000554403.1 link	n.1068+7820C>A		intron_variant	Intron 1 of 2	2
ZFHX2-AS1	ENST00000556354.5 link	n.465+7820C>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000756

AC:

AN:

1322482

Hom.:

Cov.:

AF XY:

0.0000109

AC XY:

AN XY:

645024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000955

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.74

M_CAP

Benign

0.012

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.045

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.022

Polyphen

0.19

Vest4

0.32

MutPred

0.35

Gain of catalytic residue at S2483 (P = 0);

MVP

0.41

ClinPred

0.24

GERP RS

1.6

Varity_R

0.20

gMVP

0.17

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over