rs114864530

Variant names:

• chr20-45950314-C-G
• rs114864530
• NM_022095.4:c.3392G>C

Your query was ambiguous. Multiple possible variants found:

• chr20-45950314-C-G
• chr20-45950314-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022095.4(ZNF335):​c.3392G>C​(p.Arg1131Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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. R1131K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF335 NM_022095.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22
• Publications: 0 publications found

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)

ACMG classification

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=0.21470067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF335	NM_022095.4	c.3392G>C	p.Arg1131Thr	missense_variant	Exon 22 of 28	ENST00000322927.3	NP_071378.1
ZNF335	XM_047440363.1	c.3392G>C	p.Arg1131Thr	missense_variant	Exon 21 of 27		XP_047296319.1
ZNF335	XM_005260504.5	c.3389G>C	p.Arg1130Thr	missense_variant	Exon 21 of 27		XP_005260561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF335	ENST00000322927.3	c.3392G>C	p.Arg1131Thr	missense_variant	Exon 22 of 28	1	NM_022095.4	ENSP00000325326.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 1131 of the ZNF335 protein (p.Arg1131Thr). This variant has not been reported in the literature in individuals affected with ZNF335-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.14
Sift	Uncertain	0.015	D
Sift4G	Benign	0.11	T
Polyphen		0.96	D
Vest4		0.24
MutPred		0.46		Gain of phosphorylation at R1131 (P = 0.0082);
MVP		0.47
MPC		0.23
ClinPred		0.58	D
GERP RS		2.9
Varity_R		0.090
gMVP		0.27
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs114864530; hg19: chr20-44578953;