19-21034161-A-G

Position:

• chr19-21034161-A-G

Variant summary

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

The ENST00000261560.10(ZNF430):​c.299A>G​(p.His100Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,576 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF430 ENST00000261560.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.369

Genes affected

ZNF430 (HGNC:20808): (zinc finger protein 430) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in substantia nigra development. Predicted to be located 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=0.08335647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF430	NM_025189.4	c.299A>G	p.His100Arg	missense_variant	4/5	ENST00000261560.10	NP_079465.3
ZNF430	NM_001172671.2	c.296A>G	p.His99Arg	missense_variant	4/5		NP_001166142.1
ZNF430	XM_047439464.1	c.206A>G	p.His69Arg	missense_variant	3/4		XP_047295420.1
ZNF430	XM_047439465.1	c.203A>G	p.His68Arg	missense_variant	3/4		XP_047295421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF430	ENST00000261560.10	c.299A>G	p.His100Arg	missense_variant	4/5	1	NM_025189.4	ENSP00000261560.4
ZNF430	ENST00000594110.5	c.299A>G	p.His100Arg	missense_variant	4/5	4		ENSP00000473069.1
ZNF430	ENST00000599548.5	c.299A>G	p.His100Arg	missense_variant	4/5	5		ENSP00000471313.1
ZNF430	ENST00000595401.1	c.296A>G	p.His99Arg	missense_variant	4/4	2		ENSP00000469148.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460576 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Aug 09, 2021

The c.299A>G (p.H100R) alteration is located in exon 4 (coding exon 4) of the ZNF430 gene. This alteration results from a A to G substitution at nucleotide position 299, causing the histidine (H) at amino acid position 100 to be replaced by an arginine (R). 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	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.5
DANN	Benign	0.47
DEOGEN2	Benign	0.077	T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.52	T;T;T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.083	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.14	N;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.6	D;.;.;.
REVEL	Benign	0.037
Sift	Benign	0.049	D;.;.;.
Sift4G	Benign	0.17	T;T;T;D
Polyphen		0.46	P;.;.;.
Vest4		0.26
MutPred		0.25		Loss of ubiquitination at K98 (P = 0.0547);Loss of ubiquitination at K98 (P = 0.0547);Loss of ubiquitination at K98 (P = 0.0547);.;
MVP		0.092
MPC		0.19
ClinPred		0.11	T
GERP RS		0.20
Varity_R		0.13
gMVP		0.044

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-21216967;