chr9-92846251-G-T

Position:

• chr9-92846251-G-T

Variant summary

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

The NM_031486.4(ZNF484):​c.2536C>A​(p.Gln846Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,958 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: 0.0000062 (0 hom.)
• Consequence: ZNF484 NM_031486.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0410

Genes affected

ZNF484 (HGNC:23385): (zinc finger protein 484) Predicted to enable DNA-binding transcription activator 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]

ENSG00000288271 (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=0.05022034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF484	NM_031486.4	c.2536C>A	p.Gln846Lys	missense_variant	5/5	ENST00000375495.8	NP_113674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF484	ENST00000375495.8	c.2536C>A	p.Gln846Lys	missense_variant	5/5	1	NM_031486.4	ENSP00000364645.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460958 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726758

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 07, 2021

The c.2536C>A (p.Q846K) alteration is located in exon 5 (coding exon 4) of the ZNF484 gene. This alteration results from a C to A substitution at nucleotide position 2536, causing the glutamine (Q) at amino acid position 846 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	Benign	0.067
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.8
DANN	Benign	0.66
DEOGEN2	Benign	0.00049	.;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00063	N
LIST_S2	Benign	0.34	T;T;T;.
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.050	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.56	.;.;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.41	.;.;N;N
REVEL	Benign	0.018
Sift	Benign	0.95	.;.;T;T
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.0020	.;.;B;.
Vest4		0.11
MutPred		0.34		.;.;Gain of ubiquitination at Q846 (P = 0.0054);.;
MVP		0.23
MPC		0.19
ClinPred		0.070	T
GERP RS		-0.45
Varity_R		0.10
gMVP		0.14

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: rs975045199; hg19: chr9-95608533;