19-44428818-G-A

Position:

• chr19-44428818-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.1963C>T​(p.Pro655Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ZNF229 NM_014518.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13

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=0.19614354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF229	NM_014518.4	c.1963C>T	p.Pro655Ser	missense_variant	6/6	ENST00000614049.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF229	ENST00000614049.5	c.1963C>T	p.Pro655Ser	missense_variant	6/6	1	NM_014518.4	A2
ZNF229	ENST00000613197.4	c.1945C>T	p.Pro649Ser	missense_variant	6/6	1		P4
ZNF229	ENST00000620012.4	c.*2166C>T		3_prime_UTR_variant, NMD_transcript_variant	6/6	1
ZNF229	ENST00000591289.5	n.523-11272C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 19, 2022

The c.1963C>T (p.P655S) 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 1963, causing the proline (P) at amino acid position 655 to be replaced by a serine (S). 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Benign	0.071
Eigen_PC	Benign	-0.094
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T;.
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.65	D;D
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.025	D;D
Vest4		0.18
MutPred		0.37		.;Gain of MoRF binding (P = 0.0641);
MVP		0.62
ClinPred		0.87	D
GERP RS		2.4
gMVP		0.044

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: rs1971638276; hg19: chr19-44932993;