19-48282373-C-G

Variant names:

• chr19-48282373-C-G
• rs757870029
• NM_153608.4:c.12C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153608.4(ZNF114):​c.12C>G​(p.Asp4Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ZNF114 NM_153608.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.662

Genes affected

ZNF114 (HGNC:12894): (zinc finger protein 114) Enables identical protein binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04594001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF114	NM_153608.4	c.12C>G	p.Asp4Glu	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000595607.6	NP_705836.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF114	ENST00000595607.6	c.12C>G	p.Asp4Glu	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_153608.4	ENSP00000469998.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249624 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 134992

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: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460304 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726442

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000814

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.12C>G (p.D4E) alteration is located in exon 4 (coding exon 2) of the ZNF114 gene. This alteration results from a C to G substitution at nucleotide position 12, causing the aspartic acid (D) at amino acid position 4 to be replaced by a glutamic acid (E). 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	0.33
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.7
DANN	Benign	0.60
DEOGEN2	Benign	0.011	T;T;.;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.0026	.;.;T;T;T;T
M_CAP	Benign	0.00050	T
MetaRNN	Benign	0.036	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.64	N;N;.;.;N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.81	.;.;.;.;N;.
REVEL	Benign	0.041
Sift	Benign	0.82	.;.;.;.;T;.
Sift4G	Benign	0.58	T;T;T;T;T;T
Polyphen		0.45	B;B;.;.;B;.
Vest4		0.21
MutPred		0.26		Gain of catalytic residue at D4 (P = 0.0504);Gain of catalytic residue at D4 (P = 0.0504);.;.;Gain of catalytic residue at D4 (P = 0.0504);.;
MVP		0.11
MPC		0.39
ClinPred		0.025	T
GERP RS		-4.1
Varity_R		0.053
gMVP		0.077

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs757870029; hg19: chr19-48785630;