Genetic Variant NM_170686.3:c.638A>C (chr7-149166907-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_170686.3(ZNF398):c.638A>C(p.Glu213Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ZNF398
NM_170686.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.79

Variant links:

Genes affected

ZNF398 (HGNC:18373): (zinc finger protein 398) This gene encodes a member of the Kruppel family of C2H2-type zinc-finger transcription factor proteins. The encoded protein acts as a transcriptional activator. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described, but their full length sequence has not been determined. [provided by RefSeq, Jul 2008]

ZNF398 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07276374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF398	NM_170686.3 link	c.638A>C	p.Glu213Ala	missense_variant	Exon 4 of 6	ENST00000475153.6	NP_733787.1	Q8TD17-1A0A090N7S8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF398	ENST00000475153.6 link	c.638A>C	p.Glu213Ala	missense_variant	Exon 4 of 6	1	NM_170686.3	ENSP00000420418.1	Q8TD17-1
ZNF398	ENST00000426851.6 link	c.125A>C	p.Glu42Ala	missense_variant	Exon 5 of 7	1		ENSP00000389972.2	Q8TD17-2
ZNF398	ENST00000483892.5 link	c.125A>C	p.Glu42Ala	missense_variant	Exon 4 of 6	5		ENSP00000418564.1	Q8TD17-2
ZNF398	ENST00000491174.1 link	c.125A>C	p.Glu42Ala	missense_variant	Exon 5 of 7	2		ENSP00000419391.1	Q8TD17-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248872

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459472

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000899

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.638A>C (p.E213A) alteration is located in exon 4 (coding exon 4) of the ZNF398 gene. This alteration results from a A to C substitution at nucleotide position 638, causing the glutamic acid (E) at amino acid position 213 to be replaced by an alanine (A). 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

0.093

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.76

.;T;.;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.073

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

.;N;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.030

Sift

Benign

0.11

T;T;T;T

Sift4G

Uncertain

0.040

D;D;D;D

Polyphen

0.044

.;B;.;.

Vest4

0.30

MVP

0.29

MPC

0.32

ClinPred

0.12

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.25

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