3-40486832-G-A

Position:

• chr3-40486832-G-A

Variant summary

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

The NM_001145093.4(ZNF619):​c.322G>A​(p.Glu108Lys) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF619 NM_001145093.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83

Genes affected

ZNF619 (HGNC:26910): (zinc finger protein 619) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA 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]

ZNF619 (HGNC:):

ZNF620 (HGNC:28742): (zinc finger protein 620) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07473835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF619	NM_001145093.4	c.322G>A	p.Glu108Lys	missense_variant	5/5	ENST00000432264.4	NP_001138565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF619	ENST00000432264.4	c.322G>A	p.Glu108Lys	missense_variant	5/5	5	NM_001145093.4	ENSP00000388710.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 20, 2024

The c.442G>A (p.E148K) alteration is located in exon 6 (coding exon 5) of the ZNF619 gene. This alteration results from a G to A substitution at nucleotide position 442, causing the glutamic acid (E) at amino acid position 148 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	Benign	0.095
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;.;T;.;T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.72	T;T;T;T;.;.;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.075	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L;.;.;.;.;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N;N;.;N;N;N;N
REVEL	Benign	0.011
Sift	Benign	0.075	T;T;.;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T;T
Polyphen		0.27	B;.;B;.;B;.;.
Vest4		0.15
MutPred		0.37		.;.;Loss of ubiquitination at K94 (P = 0.0142);.;Loss of ubiquitination at K94 (P = 0.0142);.;.;
MVP		0.31
MPC		0.038
ClinPred		0.14	T
GERP RS		2.0
Varity_R		0.051
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-40528323;