Genetic Variant ZNF292:p.Pro90Leu (chr6-87216003-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_015021.3(ZNF292):c.269C>T(p.Pro90Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,432,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P90R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZNF292
NM_015021.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.39

Publications

0 publications found

Variant links:

Genes affected

ZNF292 (HGNC:18410): (zinc finger protein 292) This gene encodes a growth hormone-dependent, zinc finger transcription factor that functions as a tumor suppressor. Naturally occurring mutations in this gene are associated with gastric cancer, colorectal cancer, and chronic lymphocytic leukemia. [provided by RefSeq, May 2017]

ZNF292 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
intellectual developmental disorder, autosomal dominant 64
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ZNF292 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF292	NM_015021.3 link	c.269C>T	p.Pro90Leu	missense_variant	Exon 2 of 8	ENST00000369577.8	NP_055836.1	O60281-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF292	ENST00000369577.8 link	c.269C>T	p.Pro90Leu	missense_variant	Exon 2 of 8	1	NM_015021.3	ENSP00000358590.3		O60281-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1432686

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

712608

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31562

American (AMR)

AF:

0.00

AC:

AN:

35558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24196

East Asian (EAS)

AF:

0.00

AC:

AN:

39442

South Asian (SAS)

AF:

0.0000369

AC:

AN:

81284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103212

Other (OTH)

AF:

0.00

AC:

AN:

59088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

4.4

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.9

D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.045

D;D

Polyphen

1.0

D;.

Vest4

0.87

MutPred

0.58

Loss of methylation at K87 (P = 0.0491);Loss of methylation at K87 (P = 0.0491);

MVP

0.19

ClinPred

0.99

GERP RS

4.8

Varity_R

0.27

gMVP

0.42

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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6-87216003-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over