19-44428745-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014518.4(ZNF229):c.2036C>T(p.Thr679Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ZNF229 NM_014518.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.865

Genes affected

ZNF229 (HGNC:13022): (zinc finger protein 229) Predicted to enable DNA-binding transcription activator 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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22669986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF229	NM_014518.4	c.2036C>T	p.Thr679Met	missense_variant	6/6	ENST00000614049.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF229	ENST00000614049.5	c.2036C>T	p.Thr679Met	missense_variant	6/6	1	NM_014518.4	A2
ZNF229	ENST00000613197.4	c.2018C>T	p.Thr673Met	missense_variant	6/6	1		P4
ZNF229	ENST00000620012.4	c.*2239C>T		3_prime_UTR_variant, NMD_transcript_variant	6/6	1
ZNF229	ENST00000591289.5	n.523-11199C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249690 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135404

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461866 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The c.2036C>T (p.T679M) alteration is located in exon 6 (coding exon 4) of the ZNF229 gene. This alteration results from a C to T substitution at nucleotide position 2036, causing the threonine (T) at amino acid position 679 to be replaced by a methionine (M). 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	0.29
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.61	T;.
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	0.60	D;N
PrimateAI	Uncertain	0.52	T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.19
MutPred		0.29		.;Loss of phosphorylation at T679 (P = 0.0358);
MVP		0.62
ClinPred		0.88	D
GERP RS		2.8
gMVP		0.046

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

Publications

LitVar

Other links and lift over

dbSNP: rs754516445; hg19: chr19-44932920; COSMIC: COSV52159418; COSMIC: COSV52159418;