Genetic Variant ZNF805:p.Val195Leu (chr19-57253402-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001023563.4(ZNF805):c.583G>C(p.Val195Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ZNF805
NM_001023563.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.85

Publications

0 publications found

Variant links:

Genes affected

ZNF805 (HGNC:23272): (zinc finger protein 805) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF805 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042479694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF805	NM_001023563.4 link	c.583G>C	p.Val195Leu	missense_variant	Exon 4 of 4	ENST00000414468.3	NP_001018857.2
ZNF805	NM_001145078.2 link	c.184G>C	p.Val62Leu	missense_variant	Exon 3 of 3		NP_001138550.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF805	ENST00000414468.3 link	c.583G>C	p.Val195Leu	missense_variant	Exon 4 of 4	5	NM_001023563.4	ENSP00000412999.1
ZNF805	ENST00000354309.4 link	c.184G>C	p.Val62Leu	missense_variant	Exon 3 of 3	5		ENSP00000365414.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1408320

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695698

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:

31860

American (AMR)

AF:

0.00

AC:

AN:

36346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25264

East Asian (EAS)

AF:

0.00

AC:

AN:

36490

South Asian (SAS)

AF:

0.00

AC:

AN:

80218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1083874

Other (OTH)

AF:

0.00

AC:

AN:

58450

⚠️ 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.0020

(source)

DANN

Benign

0.097

DEOGEN2

Benign

0.0014

.;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.0065

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.042

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.17

.;N

PhyloP100

-2.9

PrimateAI

Benign

0.26

PROVEAN

Benign

0.48

N;N

REVEL

Benign

0.015

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.019

MutPred

0.26

.;Loss of methylation at K192 (P = 0.0831);

MVP

0.043

MPC

0.24

ClinPred

0.036

GERP RS

-8.7

Varity_R

0.031

gMVP

0.018

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over