19-44027470-G-A

Variant names:

• chr19-44027470-G-A
• rs370000724
• NM_001129996.2:c.242G>A

Variant summary

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

The NM_001129996.2(ZNF222):​c.242G>A​(p.Ser81Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: ZNF222 NM_001129996.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.25
• Publications: 1 publications found

Genes affected

ZNF222 (HGNC:13015): (zinc finger protein 222) 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]

ENSG00000267022 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.041260123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF222	NM_001129996.2	c.242G>A	p.Ser81Asn	missense_variant	Exon 3 of 4	ENST00000391960.4	NP_001123468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF222	ENST00000391960.4	c.242G>A	p.Ser81Asn	missense_variant	Exon 3 of 4	1	NM_001129996.2	ENSP00000375822.2
ENSG00000267022	ENST00000591793.1	n.242G>A		non_coding_transcript_exon_variant	Exon 3 of 11	2		ENSP00000467018.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

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: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000279 AC: 70 AN: 250544 AF XY: 0.000265

Gnomad AFR exome AF: 0.0000635

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: 0.000608

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000456 AC: 667 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.000414 AC XY: 301 AN XY: 727186

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53414

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

European-Non Finnish (NFE) AF: 0.000584 AC: 649 AN: 1111956

Other (OTH) AF: 0.000232 AC: 14 AN: 60390

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 22 AN XY: 74322

African (AFR) AF: 0.000266 AC: 11 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68020

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

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.000253

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242G>A (p.S81N) alteration is located in exon 3 (coding exon 3) of the ZNF222 gene. This alteration results from a G to A substitution at nucleotide position 242, causing the serine (S) at amino acid position 81 to be replaced by an asparagine (N). 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
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.59
DANN	Benign	0.44
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.056	T;T
M_CAP	Benign	0.00090	T
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.96	T
PhyloP100		-1.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.048
Sift	Benign	0.034	.;D
Sift4G	Benign	0.20	T;T
Vest4		0.17
MVP		0.055
MPC		0.061
ClinPred		0.043	T
GERP RS		-3.2
gMVP		0.010
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs370000724; hg19: chr19-44531622; COSMIC: COSV51827864; COSMIC: COSV51827864;