chr19-12430723-T-A

Variant names:

• chr19-12430723-T-A
• rs150109548
• NM_005815.5:c.1449A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005815.5(ZNF443):​c.1449A>T​(p.Lys483Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: ZNF443 NM_005815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0740
• Publications: 0 publications found

Genes affected

ZNF443 (HGNC:20878): (zinc finger protein 443) Zinc finger proteins (ZNFs) bind DNA and, through this binding, regulate gene transcription. Most ZNFs contain conserved C2H2 motifs and are classified as Kruppel-type zinc fingers. For a general description of these proteins, see ZNF91 (MIM 603971).[supplied by OMIM, Jul 2002]

ENSG00000268870 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03136778).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005815.5. 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
	ZNF443	NM_005815.5	MANE Select	c.1449A>T	p.Lys483Asn	missense	Exon 4 of 4	NP_005806.3	Q9Y2A4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF443	ENST00000301547.10	TSL:1 MANE Select	c.1449A>T	p.Lys483Asn	missense	Exon 4 of 4	ENSP00000301547.5	Q9Y2A4
	ENSG00000268870	ENST00000595562.1	TSL:4	c.3+10189A>T		intron	N/A	ENSP00000471613.1	M0R135

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000442 AC: 111 AN: 250876 AF XY: 0.000516

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000591 AC: 863 AN: 1461066 Hom.: 0 Cov.: 86 AF XY: 0.000636 AC XY: 462 AN XY: 726850

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

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.0000895 AC: 4 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00103 AC: 89 AN: 86226

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.000624 AC: 693 AN: 1111410

Other (OTH) AF: 0.000613 AC: 37 AN: 60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74472

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

African (AFR) AF: 0.0000481 AC: 2 AN: 41554

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ 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: 0.000758 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

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	Uncertain	0.43
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.00037	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.074
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.057
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.61		Loss of methylation at K483 (P = 0.0037)
MVP		0.28
MPC		0.26
ClinPred		0.11	T
GERP RS		-1.5
Varity_R		0.17
gMVP		0.033
Mutation Taster		=100/0	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: rs150109548; hg19: chr19-12541537;