Genetic Variant ZNF875:p.Thr30Lys (chr19-37344773-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181786.4(ZNF875):c.89C>A(p.Thr30Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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. T30M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ZNF875
NM_181786.4 missense, splice_region

Scores

Splicing: ADA: 0.0001561

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.605

Publications

0 publications found

Variant links:

Genes affected

ZNF875 (HGNC:4928): (zinc finger protein 875) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF875 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.116502166).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181786.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF875	NM_001353803.2	MANE Select	c.34-2417C>A		intron	N/A	NP_001340732.1	P10072-2
ZNF875	NM_181786.4		c.89C>A	p.Thr30Lys	missense splice_region	Exon 3 of 6	NP_861451.1	P10072-1
ZNF875	NM_001329761.2		c.34-2417C>A		intron	N/A	NP_001316690.1	K7EPW3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF875	ENST00000324411.8	TSL:1	c.89C>A	p.Thr30Lys	missense splice_region	Exon 3 of 6	ENSP00000315505.3	P10072-1
ZNF875	ENST00000392153.8	TSL:1 MANE Select	c.34-2417C>A		intron	N/A	ENSP00000375994.3	P10072-2
ZNF875	ENST00000591259.5	TSL:1	c.34-2417C>A		intron	N/A	ENSP00000466472.1	K7EME6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.24e-7

AC:

AN:

1381658

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692118

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:

31566

American (AMR)

AF:

0.00

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25654

East Asian (EAS)

AF:

0.00

AC:

AN:

39312

South Asian (SAS)

AF:

0.00

AC:

AN:

84636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

9.62e-7

AC:

AN:

1039224

Other (OTH)

AF:

0.00

AC:

AN:

57670

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.35

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.018

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.21

M_CAP

Benign

0.0017

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

-0.60

PrimateAI

Benign

0.43

PROVEAN

Benign

0.54

REVEL

Benign

0.015

Sift

Benign

0.16

Sift4G

Benign

0.88

Polyphen

0.16

Vest4

0.12

MutPred

0.65

Gain of ubiquitination at T30 (P = 0.0247)

MVP

0.040

MPC

0.033

ClinPred

0.075

GERP RS

0.12

Varity_R

0.039

gMVP

0.061

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

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