Genetic Variant NM_018335.6:c.175C>G (chr14-102319940-C-G) – 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_018335.6(ZNF839):c.175C>G(p.Pro59Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000918 in 1,198,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P59R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

ZNF839
NM_018335.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.22

Publications

0 publications found

Variant links:

Genes affected

ZNF839 (HGNC:20345): (zinc finger protein 839) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ZNF839 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=0.17679578).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018335.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF839	NM_018335.6	MANE Select	c.175C>G	p.Pro59Ala	missense	Exon 1 of 8	NP_060805.3	A8K0R7-5
ZNF839	NM_001385065.1		c.175C>G	p.Pro59Ala	missense	Exon 1 of 7	NP_001371994.1
ZNF839	NM_001385072.1		c.175C>G	p.Pro59Ala	missense	Exon 1 of 8	NP_001372001.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF839	ENST00000442396.7	TSL:5 MANE Select	c.175C>G	p.Pro59Ala	missense	Exon 1 of 8	ENSP00000399863.2	A8K0R7-5
ZNF839	ENST00000892181.1		c.175C>G	p.Pro59Ala	missense	Exon 1 of 7	ENSP00000562240.1
ZNF839	ENST00000892182.1		c.175C>G	p.Pro59Ala	missense	Exon 1 of 8	ENSP00000562241.1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000858

AC:

AN:

1049184

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

506640

show subpopulations

African (AFR)

AF:

0.0000979

AC:

AN:

20426

American (AMR)

AF:

0.00

AC:

AN:

8904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12788

East Asian (EAS)

AF:

0.00

AC:

AN:

18918

South Asian (SAS)

AF:

0.00

AC:

AN:

29366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2674

European-Non Finnish (NFE)

AF:

0.00000779

AC:

AN:

898896

Other (OTH)

AF:

0.00

AC:

AN:

39438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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

AF:

0.0000134

AC:

AN:

149440

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72858

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41130

American (AMR)

AF:

0.00

AC:

AN:

15042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

5102

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67050

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.700

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

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

Benign

0.070

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.4

(source)

DANN

Benign

0.64

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.34

M_CAP

Benign

0.0068

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

PhyloP100

1.2

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.56

REVEL

Benign

0.078

Sift

Benign

0.21

Sift4G

Benign

0.13

Polyphen

0.93

Vest4

0.19

MutPred

0.28

Loss of loop (P = 0.0022)

MVP

0.31

MPC

0.10

ClinPred

0.48

GERP RS

2.7

PromoterAI

0.067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.071

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over