19-21536715-G-C

Position:

• chr19-21536715-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001415.4(ZNF429):​c.662G>C​(p.Arg221Thr) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF429 NM_001001415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0350

Genes affected

ZNF429 (HGNC:20817): (zinc finger protein 429) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15387297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF429	NM_001001415.4	c.662G>C	p.Arg221Thr	missense_variant	4/4	ENST00000358491.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF429	ENST00000358491.9	c.662G>C	p.Arg221Thr	missense_variant	4/4	3	NM_001001415.4	P1
ZNF429	ENST00000597078.5	c.227-5049G>C		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.662G>C (p.R221T) alteration is located in exon 4 (coding exon 4) of the ZNF429 gene. This alteration results from a G to C substitution at nucleotide position 662, causing the arginine (R) at amino acid position 221 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.7
DANN	Benign	0.76
DEOGEN2	Benign	0.040	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.25	T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.032
Sift	Uncertain	0.023	D;.
Sift4G	Uncertain	0.024	D;T
Polyphen		0.19	B;.
Vest4		0.36
MutPred		0.61		Loss of MoRF binding (P = 0.0345);Loss of MoRF binding (P = 0.0345);
MVP		0.26
MPC		0.032
ClinPred		0.11	T
GERP RS		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.026

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-21719517;