19-52321620-A-G

Position:

• chr19-52321620-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144684.4(ZNF480):​c.370A>G​(p.Ile124Val) 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 1,455,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: ZNF480 NM_144684.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.405

Genes affected

ZNF480 (HGNC:23305): (zinc finger protein 480) 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. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269535 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06405249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF480	NM_144684.4	c.370A>G	p.Ile124Val	missense_variant	5/5	ENST00000595962.6	NP_653285.2
ZNF480	NM_001297624.2	c.241A>G	p.Ile81Val	missense_variant	4/4		NP_001284553.1
ZNF480	NM_001297625.2	c.139A>G	p.Ile47Val	missense_variant	4/4		NP_001284554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF480	ENST00000595962.6	c.370A>G	p.Ile124Val	missense_variant	5/5	1	NM_144684.4	ENSP00000471754.1
ZNF480	ENST00000468240.6	n.370A>G		non_coding_transcript_exon_variant	5/6	2		ENSP00000417424.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455576 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 723096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Feb 10, 2022

The c.370A>G (p.I124V) alteration is located in exon 5 (coding exon 4) of the ZNF480 gene. This alteration results from a A to G substitution at nucleotide position 370, causing the isoleucine (I) at amino acid position 124 to be replaced by a valine (V). 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	0.065
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.22
DANN	Benign	0.16
DEOGEN2	Benign	0.011	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.078	T;T;T
M_CAP	Benign	0.00097	T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.48	.;N;N
REVEL	Benign	0.012
Sift	Benign	0.62	.;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.068	B;B;.
Vest4		0.071
MutPred		0.29		Gain of methylation at K125 (P = 0.0872);.;.;
MVP		0.18
MPC		0.049
ClinPred		0.022	T
GERP RS		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
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

LitVar

Other links and lift over

dbSNP: rs1983814152; hg19: chr19-52824873;