rs763578981

Variant names:

• chr19-43846995-G-A
• rs763578981
• NM_181845.2:c.394G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181845.2(ZNF283):​c.394G>A​(p.Glu132Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,561,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ZNF283 NM_181845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.598
• Publications: 0 publications found

Genes affected

ZNF283 (HGNC:13077): (zinc finger protein 283) 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. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098421544).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181845.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF283	NM_181845.2	MANE Select	c.394G>A	p.Glu132Lys	missense	Exon 7 of 7	NP_862828.1	Q8N7M2
	ZNF283	NM_001297752.2		c.-24G>A		5_prime_UTR	Exon 6 of 6	NP_001284681.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF283	ENST00000618787.5	TSL:2 MANE Select	c.394G>A	p.Glu132Lys	missense	Exon 7 of 7	ENSP00000484852.1	Q8N7M2
	ZNF283	ENST00000324461.9	TSL:1	c.394G>A	p.Glu132Lys	missense	Exon 4 of 4	ENSP00000327314.7	Q8N7M2
	ZNF283	ENST00000650832.1		c.286G>A	p.Glu96Lys	missense	Exon 7 of 7	ENSP00000498705.1	A0A494C0U8

Frequencies

GnomAD3 genomes AF: 0.00000720 AC: 1 AN: 138818 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000157

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000204 AC: 4 AN: 196104 AF XY: 0.0000189

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000459

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000211 AC: 30 AN: 1422540 Hom.: 0 Cov.: 33 AF XY: 0.0000142 AC XY: 10 AN XY: 706244

African (AFR) AF: 0.00 AC: 0 AN: 31980

American (AMR) AF: 0.00 AC: 0 AN: 38828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24636

East Asian (EAS) AF: 0.00 AC: 0 AN: 38258

South Asian (SAS) AF: 0.00 AC: 0 AN: 81948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.0000266 AC: 29 AN: 1091402

Other (OTH) AF: 0.0000172 AC: 1 AN: 58284

GnomAD4 genome AF: 0.00000720 AC: 1 AN: 138818 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 67330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 36718

American (AMR) AF: 0.00 AC: 0 AN: 14384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3282

East Asian (EAS) AF: 0.00 AC: 0 AN: 4854

South Asian (SAS) AF: 0.00 AC: 0 AN: 3780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000157 AC: 1 AN: 63868

Other (OTH) AF: 0.00 AC: 0 AN: 1928

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000902 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.51	N
PhyloP100		0.60
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.084
Sift	Benign	0.17	T
Sift4G	Benign	0.23	T
Polyphen		0.38	B
Vest4		0.32
MutPred		0.34		Gain of ubiquitination at E132 (P = 0.0114)
MVP		0.52
MPC		0.35
ClinPred		0.11	T
GERP RS		3.5
Varity_R		0.20
gMVP		0.083
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs763578981; hg19: chr19-44351147;