chr19-44027458-T-A

Variant names:

• chr19-44027458-T-A
• NM_001129996.2:c.230T>A

Variant summary

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

The NM_001129996.2(ZNF222):​c.230T>A​(p.Met77Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZNF222 NM_001129996.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.327
• Publications: 0 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: 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=0.21331719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF222	NM_001129996.2	c.230T>A	p.Met77Lys	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.230T>A	p.Met77Lys	missense_variant	Exon 3 of 4	1	NM_001129996.2	ENSP00000375822.2
ENSG00000267022	ENST00000591793.1	n.230T>A		non_coding_transcript_exon_variant	Exon 3 of 11	2		ENSP00000467018.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230T>A (p.M77K) alteration is located in exon 3 (coding exon 3) of the ZNF222 gene. This alteration results from a T to A substitution at nucleotide position 230, causing the methionine (M) at amino acid position 77 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
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.87
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.00098	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.33
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.4	.;D
REVEL	Benign	0.058
Sift	Benign	0.12	.;T
Sift4G	Benign	0.33	T;T
Vest4		0.45
MutPred		0.48		Gain of ubiquitination at M77 (P = 0.0155);Gain of ubiquitination at M77 (P = 0.0155);
MVP		0.040
MPC		0.23
ClinPred		0.34	T
GERP RS		-0.88
gMVP		0.11
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

hg19: chr19-44531610;