19-8512677-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001146175.2(ZNF414):c.351C>G(p.Cys117Trp) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0370

Genes affected

ZNF414 (HGNC:20630): (zinc finger protein 414) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3021316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF414	NM_001146175.2	c.351C>G	p.Cys117Trp	missense_variant	3/8	ENST00000393927.9
ZNF414	NM_032370.3	c.351C>G	p.Cys117Trp	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF414	ENST00000393927.9	c.351C>G	p.Cys117Trp	missense_variant	3/8	1	NM_001146175.2	P1
ZNF414	ENST00000255616.8	c.351C>G	p.Cys117Trp	missense_variant	3/6	1
ZNF414	ENST00000599379.1	c.38C>G	p.Ala13Gly	missense_variant, NMD_transcript_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jul 05, 2023

The c.351C>G (p.C117W) alteration is located in exon 3 (coding exon 3) of the ZNF414 gene. This alteration results from a C to G substitution at nucleotide position 351, causing the cysteine (C) at amino acid position 117 to be replaced by a tryptophan (W). 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	0.32
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.073
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.029	D;D
Polyphen		0.68	.;P
Vest4		0.52
MutPred		0.39		Loss of catalytic residue at S119 (P = 0.1428);Loss of catalytic residue at S119 (P = 0.1428);
MVP		0.42
MPC		0.75
ClinPred		0.49	T
GERP RS		3.8
Varity_R		0.17
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-8577561;