19-8510958-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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=0.22393489).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF414	NM_001146175.2	c.992C>A	p.Ala331Asp	missense_variant	7/8	ENST00000393927.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF414	ENST00000393927.9	c.992C>A	p.Ala331Asp	missense_variant	7/8	1	NM_001146175.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1104756 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 526358

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 06, 2022

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	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.69	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.067
Sift	Benign	0.11	T
Sift4G	Uncertain	0.036	D
Vest4		0.15
MutPred		0.55		Loss of helix (P = 0.0444);
MVP		0.39
MPC		0.71
ClinPred		0.95	D
GERP RS		4.5
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-8575842;