chr20-45950453-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_022095.4(ZNF335):c.3332G>T(p.Arg1111Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1111H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ZNF335
NM_022095.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.26

Publications

8 publications found

Variant links:

Genes affected

ZNF335 (HGNC:15807): (zinc finger protein 335) The protein encoded by this gene enhances transcriptional activation by ligand-bound nuclear hormone receptors. However, it does this not by direct interaction with the receptor, but by direct interaction with the nuclear hormone receptor transcriptional coactivator NRC. The encoded protein may function by altering local chromatin structure. [provided by RefSeq, Jul 2008]

ZNF335 Gene-Disease associations (from GenCC):

microcephalic primordial dwarfism due to ZNF335 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ZNF335 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-45950453-C-T is described in CliVar as Pathogenic. Clinvar id is 40116.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 20-45950453-C-A is Pathogenic according to our data. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45950453-C-A is described in CliVar as Pathogenic. Clinvar id is 225017.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF335	NM_022095.4 link	c.3332G>T	p.Arg1111Leu	missense_variant, splice_region_variant	Exon 21 of 28	ENST00000322927.3	NP_071378.1	Q9H4Z2-1Q8IW09
ZNF335	XM_047440363.1 link	c.3332G>T	p.Arg1111Leu	missense_variant, splice_region_variant	Exon 20 of 27		XP_047296319.1
ZNF335	XM_005260504.5 link	c.3329G>T	p.Arg1110Leu	missense_variant, splice_region_variant	Exon 20 of 27		XP_005260561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF335	ENST00000322927.3 link	c.3332G>T	p.Arg1111Leu	missense_variant, splice_region_variant	Exon 21 of 28	1	NM_022095.4	ENSP00000325326.2		Q9H4Z2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Oct 23, 2013

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

7.3

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.29

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.85

MutPred

0.55

Loss of catalytic residue at R1111 (P = 0.0078);

MVP

0.72

MPC

0.74

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.60

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.53

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.53

Position offset: 0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over