19-52314198-G-A

Position:

• chr19-52314198-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144684.4(ZNF480):​c.118G>A​(p.Glu40Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: ZNF480 NM_144684.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF480	NM_144684.4	c.118G>A	p.Glu40Lys	missense_variant	3/5	ENST00000595962.6	NP_653285.2
ZNF480	NM_001297624.2	c.118G>A	p.Glu40Lys	missense_variant	3/4		NP_001284553.1
ZNF480	NM_001297625.2	c.-32-1636G>A		intron_variant			NP_001284554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF480	ENST00000595962.6	c.118G>A	p.Glu40Lys	missense_variant	3/5	1	NM_144684.4	ENSP00000471754.1
ZNF480	ENST00000468240.6	n.118G>A		non_coding_transcript_exon_variant	3/6	2		ENSP00000417424.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 29

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

Oct 28, 2023

The c.118G>A (p.E40K) alteration is located in exon 3 (coding exon 2) of the ZNF480 gene. This alteration results from a G to A substitution at nucleotide position 118, causing the glutamic acid (E) at amino acid position 40 to be replaced by a lysine (K). 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	Pathogenic	0.61
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.084
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0045	T
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	4.0	H;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.2	.;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	.;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.50
MutPred		0.87		Gain of methylation at E40 (P = 0.0117);Gain of methylation at E40 (P = 0.0117);Gain of methylation at E40 (P = 0.0117);
MVP		0.37
MPC		0.36
ClinPred		0.99	D
GERP RS		2.0
Varity_R		0.48
gMVP		0.59

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: chr19-52817451;