Genetic Variant ZNF414:p.Ala331Asp (chr19-8510958-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001146175.2(ZNF414):c.992C>A(p.Ala331Asp) 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZNF414
NM_001146175.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22393489).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2 link	c.992C>A	p.Ala331Asp	missense_variant	Exon 7 of 8	ENST00000393927.9	NP_001139647.1	Q96IQ9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9 link	c.992C>A	p.Ala331Asp	missense_variant	Exon 7 of 8	1	NM_001146175.2	ENSP00000377504.3		Q96IQ9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1104756

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

526358

African (AFR)

AF:

0.00

AC:

AN:

22988

American (AMR)

AF:

0.00

AC:

AN:

9046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14760

East Asian (EAS)

AF:

0.00

AC:

AN:

26478

South Asian (SAS)

AF:

0.00

AC:

AN:

27754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3128

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

931836

Other (OTH)

AF:

0.00

AC:

AN:

44436

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 06, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.992C>A (p.A331D) alteration is located in exon 7 (coding exon 7) of the ZNF414 gene. This alteration results from a C to A substitution at nucleotide position 992, causing the alanine (A) at amino acid position 331 to be replaced by an aspartic acid (D). 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

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.030

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

PhyloP100

2.5

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.16

REVEL

Benign

0.067

Sift

Benign

0.11

Sift4G

Uncertain

0.036

Vest4

0.15

MutPred

0.55

Loss of helix (P = 0.0444);

MVP

0.39

MPC

0.71

ClinPred

0.95

GERP RS

4.5

gMVP

0.28

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over