chr19-52315854-A-G

Variant names:

• chr19-52315854-A-G
• rs1436534609
• NM_144684.4:c.220A>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.220A>G​(p.Asn74Asp) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF480 NM_144684.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.998

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=0.063372195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF480	NM_144684.4	c.220A>G	p.Asn74Asp	missense_variant	Exon 4 of 5	ENST00000595962.6	NP_653285.2
ZNF480	NM_001297625.2	c.-12A>G		5_prime_UTR_variant	Exon 3 of 4		NP_001284554.1
ZNF480	NM_001297624.2	c.199+1575A>G		intron_variant	Intron 3 of 3		NP_001284553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF480	ENST00000595962.6	c.220A>G	p.Asn74Asp	missense_variant	Exon 4 of 5	1	NM_144684.4	ENSP00000471754.1
ZNF480	ENST00000468240.6	n.220A>G		non_coding_transcript_exon_variant	Exon 4 of 6	2		ENSP00000417424.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250540 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459860 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726388

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.220A>G (p.N74D) alteration is located in exon 4 (coding exon 3) of the ZNF480 gene. This alteration results from a A to G substitution at nucleotide position 220, causing the asparagine (N) at amino acid position 74 to be replaced by an aspartic acid (D). 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	0.074
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.63
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.014	T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.060	N;.
PrimateAI	Uncertain	0.50	T
Sift4G	Benign	0.52	T;T
Polyphen		0.0090	B;.
Vest4		0.092
MutPred		0.38		Gain of phosphorylation at S77 (P = 0.1171);Gain of phosphorylation at S77 (P = 0.1171);
MVP		0.092
MPC		0.060
ClinPred		0.020	T
GERP RS		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.014

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

LitVar

Other links and lift over

dbSNP: rs1436534609; hg19: chr19-52819107;