Genetic Variant NM_022095.4:c.2063G>C (chr20-45959391-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022095.4(ZNF335):c.2063G>C(p.Arg688Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,546 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R688W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ZNF335
NM_022095.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.90

Publications

3 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022095.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF335	NM_022095.4	MANE Select	c.2063G>C	p.Arg688Pro	missense	Exon 15 of 28	NP_071378.1	Q9H4Z2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF335	ENST00000322927.3	TSL:1 MANE Select	c.2063G>C	p.Arg688Pro	missense	Exon 15 of 28	ENSP00000325326.2	Q9H4Z2-1
ZNF335	ENST00000944756.1		c.2063G>C	p.Arg688Pro	missense	Exon 15 of 28	ENSP00000614815.1
ZNF335	ENST00000862676.1		c.2060G>C	p.Arg687Pro	missense	Exon 14 of 27	ENSP00000532735.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.21e-7

AC:

AN:

1387546

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

687090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30482

American (AMR)

AF:

0.00

AC:

AN:

38008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24190

East Asian (EAS)

AF:

0.00

AC:

AN:

35092

South Asian (SAS)

AF:

0.00

AC:

AN:

78796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5530

European-Non Finnish (NFE)

AF:

9.37e-7

AC:

AN:

1066744

Other (OTH)

AF:

0.00

AC:

AN:

56638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

PhyloP100

2.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.7

REVEL

Benign

0.16

Sift

Uncertain

0.014

Sift4G

Uncertain

0.032

Polyphen

0.99

Vest4

0.60

MutPred

0.51

Loss of MoRF binding (P = 0.0059)

MVP

0.61

MPC

0.51

ClinPred

0.88

GERP RS

5.0

Varity_R

0.33

gMVP

0.77

Mutation Taster

=73/27

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over