Variant chr19-8510734-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001146175.2(ZNF414):c.1130C>T(p.Pro377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 1,549,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ZNF414
NM_001146175.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.75

Variant links:

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]

ZNF414 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.010082096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF414	NM_001146175.2 link	c.1130C>T	p.Pro377Leu	missense_variant	8/8	ENST00000393927.9	NP_001139647.1	Q96IQ9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9 link	c.1130C>T	p.Pro377Leu	missense_variant	8/8	1	NM_001146175.2	ENSP00000377504.3		Q96IQ9-2
ZNF414	ENST00000596772 link	c.*64C>T		3_prime_UTR_variant	3/3	2		ENSP00000471378.1		M0R0Q5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000655

AC:

AN:

152772

Hom.:

AF XY:

0.00

AC XY:

AN XY:

81196

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000413

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000358

AC:

AN:

1397790

Hom.:

Cov.:

AF XY:

0.00000580

AC XY:

AN XY:

689430

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000562

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000253

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000410

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.1130C>T (p.P377L) alteration is located in exon 8 (coding exon 8) of the ZNF414 gene. This alteration results from a C to T substitution at nucleotide position 1130, causing the proline (P) at amino acid position 377 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

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.0

DANN

Benign

0.91

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0090

LIST_S2

Benign

0.59

M_CAP

Benign

0.0073

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.99

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.2

REVEL

Benign

0.035

Sift

Benign

0.065

Sift4G

Benign

0.094

Vest4

0.098

MutPred

0.17

Loss of methylation at K374 (P = 0.0578);

MVP

0.055

MPC

0.32

ClinPred

0.046

GERP RS

-5.0

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over