NM_015428.4:c.566A>G

Variant names:

• chr19-50045009-A-G
• rs779535416
• NM_015428.4:c.566A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015428.4(ZNF473):​c.566A>G​(p.Glu189Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E189K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ZNF473 NM_015428.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0650
• Publications: 0 publications found

Genes affected

ZNF473 (HGNC:23239): (zinc finger protein 473) This gene encodes a member of the Krueppel C2H2-type zinc-finger family of proteins. The encoded protein, a component of the U7 snRNP complex, plays a role in histone 3'-end pre-mRNA processing and may be required for cell cycle progression to S phase. Expression level and methylation status of this gene may be correlated with bone mineral density. [provided by RefSeq, Jul 2016]

ENSG00000269091 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06212315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF473	NM_015428.4	c.566A>G	p.Glu189Gly	missense_variant	Exon 5 of 5	ENST00000270617.8	NP_056243.1
ZNF473	NM_001006656.4	c.566A>G	p.Glu189Gly	missense_variant	Exon 5 of 5		NP_001006657.1
ZNF473	NM_001308424.3	c.530A>G	p.Glu177Gly	missense_variant	Exon 4 of 4		NP_001295353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF473	ENST00000270617.8	c.566A>G	p.Glu189Gly	missense_variant	Exon 5 of 5	1	NM_015428.4	ENSP00000270617.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 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: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251458 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.566A>G (p.E189G) alteration is located in exon 5 (coding exon 4) of the ZNF473 gene. This alteration results from a A to G substitution at nucleotide position 566, causing the glutamic acid (E) at amino acid position 189 to be replaced by a glycine (G). 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	0.19
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.5
DANN	Benign	0.74
DEOGEN2	Benign	0.0038	T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.35	.;.;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N;N;.
PhyloP100		0.065
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.5	.;N;N;N
REVEL	Benign	0.024
Sift	Benign	0.17	.;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.050
MutPred		0.23		Loss of stability (P = 0.0272);Loss of stability (P = 0.0272);Loss of stability (P = 0.0272);.;
MVP		0.068
MPC		0.33
ClinPred		0.0097	T
GERP RS		2.1
Varity_R		0.054
gMVP		0.065
Mutation Taster		=99/1	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: rs779535416; hg19: chr19-50548266;