19-48286757-A-G

Position:

• chr19-48286757-A-G

Variant summary

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

The NM_153608.4(ZNF114):​c.1133A>G​(p.His378Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF114 NM_153608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF114	NM_153608.4	c.1133A>G	p.His378Arg	missense_variant	6/6	ENST00000595607.6	NP_705836.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF114	ENST00000595607.6	c.1133A>G	p.His378Arg	missense_variant	6/6	1	NM_153608.4	ENSP00000469998	P1
ZNF114	ENST00000315849.5	c.1133A>G	p.His378Arg	missense_variant	5/5	2		ENSP00000318898	P1
ZNF114	ENST00000600687.5	c.1133A>G	p.His378Arg	missense_variant	5/5	5		ENSP00000471727	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Feb 09, 2023

The c.1133A>G (p.H378R) alteration is located in exon 5 (coding exon 3) of the ZNF114 gene. This alteration results from a A to G substitution at nucleotide position 1133, causing the histidine (H) at amino acid position 378 to be replaced by an arginine (R). 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	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D;D;D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	.;.;T
M_CAP	Benign	0.0034	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	0.099	D
MutationAssessor	Pathogenic	3.1	M;M;M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.8	.;.;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	.;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.37
MutPred		0.60		Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);Gain of MoRF binding (P = 0.0073);
MVP		0.95
MPC		0.58
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.39
gMVP		0.18

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: rs758399097; hg19: chr19-48790014;