19-11903672-G-A

Position:

• chr19-11903672-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001364730.1(ZNF69):​c.163G>A​(p.Glu55Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF69 NM_001364730.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.35

Genes affected

ZNF69 (HGNC:13138): (zinc finger protein 69) Enables identical protein binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF69	NM_001364730.1	c.163G>A	p.Glu55Lys	missense_variant	2/4	ENST00000429654.7	NP_001351659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF69	ENST00000429654.7	c.163G>A	p.Glu55Lys	missense_variant	2/4	2	NM_001364730.1	ENSP00000402985.2
ZNF69	ENST00000340180.5	c.121G>A	p.Glu41Lys	missense_variant	2/5	1		ENSP00000345333.5
ZNF69	ENST00000445911.5	c.121G>A	p.Glu41Lys	missense_variant	2/4	2		ENSP00000388784.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

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

Jun 17, 2024

The c.121G>A (p.E41K) alteration is located in exon 2 (coding exon 2) of the ZNF69 gene. This alteration results from a G to A substitution at nucleotide position 121, causing the glutamic acid (E) at amino acid position 41 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
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.084	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.00051	T
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.5	H;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.56
MutPred		0.83		.;Gain of MoRF binding (P = 0.0079);Gain of MoRF binding (P = 0.0079);
MVP		0.10
MPC		0.45
ClinPred		0.99	D
GERP RS		-0.20
Varity_R		0.50
gMVP		0.24

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: rs916433326; hg19: chr19-12014487;