19-8511820-G-A

Variant summary

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

The NM_001146175.2(ZNF414):c.671C>T(p.Pro224Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,248,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.177

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07638338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF414	NM_001146175.2	c.671C>T	p.Pro224Leu	missense_variant	5/8	ENST00000393927.9
ZNF414	NM_032370.3	c.671C>T	p.Pro224Leu	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF414	ENST00000393927.9	c.671C>T	p.Pro224Leu	missense_variant	5/8	1	NM_001146175.2	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000128 AC: 16 AN: 1248558 Hom.: 0 Cov.: 41 AF XY: 0.00000826 AC XY: 5 AN XY: 605526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000695

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000147

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

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

Dec 21, 2022

The c.671C>T (p.P224L) alteration is located in exon 5 (coding exon 5) of the ZNF414 gene. This alteration results from a C to T substitution at nucleotide position 671, causing the proline (P) at amino acid position 224 to be replaced by a leucine (L). 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	0.082
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	9.9
Dann	Benign	0.95
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.62	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.029
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.32	.;B
Vest4		0.13
MutPred		0.20		Loss of catalytic residue at P223 (P = 0.0165);Loss of catalytic residue at P223 (P = 0.0165);
MVP		0.21
MPC		0.29
ClinPred		0.21	T
GERP RS		1.1
Varity_R		0.039
gMVP		0.47

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: rs1041470351; hg19: chr19-8576704;