Variant 14-23522511-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033400.3(ZFHX2):c.7170G>T(p.Gln2390His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,379,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFHX2	NM_033400.3 linkuse as main transcript	c.7170G>T	p.Gln2390His	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.7170G>T	p.Gln2390His	missense_variant	10/10	5	NM_033400.3	ENSP00000413418	P1	Q9C0A1-1
ZFHX2-AS1	ENST00000553985.1 linkuse as main transcript	n.238+8095C>A		intron_variant, non_coding_transcript_variant		2
ZFHX2-AS1	ENST00000554403.1 linkuse as main transcript	n.1068+8095C>A		intron_variant, non_coding_transcript_variant		2
ZFHX2-AS1	ENST00000556354.5 linkuse as main transcript	n.465+8095C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000290

AC:

AN:

1379408

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

680114

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:

0.00000279

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.00000756

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

Feb 13, 2024

The c.7170G>T (p.Q2390H) alteration is located in exon 10 (coding exon 9) of the ZFHX2 gene. This alteration results from a G to T substitution at nucleotide position 7170, causing the glutamine (Q) at amino acid position 2390 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

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.44

Sift

Benign

0.058

Sift4G

Benign

0.079

Polyphen

0.62

Vest4

0.65

MutPred

0.32

Gain of catalytic residue at L2392 (P = 2e-04);

MVP

0.48

ClinPred

0.90

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.34

gMVP

0.73

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