Genetic Variant ZFHX2:p.Phe2475Cys (chr14-23522257-A-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_033400.3(ZFHX2):c.7424T>G(p.Phe2475Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000526 in 1,331,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000053 ( 0 hom. )

Consequence

ZFHX2
NM_033400.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

BS2

High AC in GnomAdExome4 at 7 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033400.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFHX2	NM_033400.3	MANE Select	c.7424T>G	p.Phe2475Cys	missense	Exon 10 of 10	NP_207646.2	A0A2P1H683
THTPA	NR_046051.1		n.465+7841A>C		intron	N/A
THTPA	NR_046052.1		n.245+7841A>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFHX2	ENST00000419474.5	TSL:5 MANE Select	c.7424T>G	p.Phe2475Cys	missense	Exon 10 of 10	ENSP00000413418.2	Q9C0A1-1
ZFHX2-AS1	ENST00000553985.1	TSL:2	n.238+7841A>C		intron	N/A
ZFHX2-AS1	ENST00000554403.1	TSL:2	n.1068+7841A>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000526

AC:

AN:

1331712

Hom.:

Cov.:

AF XY:

0.00000461

AC XY:

AN XY:

650462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30302

American (AMR)

AF:

0.00

AC:

AN:

30400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21434

East Asian (EAS)

AF:

0.00

AC:

AN:

35280

South Asian (SAS)

AF:

0.0000142

AC:

AN:

70552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5394

European-Non Finnish (NFE)

AF:

0.00000571

AC:

AN:

1051054

Other (OTH)

AF:

0.00

AC:

AN:

55542

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.71

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.5

PhyloP100

1.1

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.9

REVEL

Benign

0.27

Sift

Benign

0.033

Sift4G

Uncertain

0.036

Polyphen

1.0

Vest4

0.69

MutPred

0.43

Gain of catalytic residue at S2480 (P = 0)

MVP

0.51

ClinPred

0.98

GERP RS

5.0

Varity_R

0.28

gMVP

0.31

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over