chr19-8510896-G-T

Variant names:

• chr19-8510896-G-T
• rs993166225
• NM_001146175.2:c.1054C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001146175.2(ZNF414):​c.1054C>A​(p.Pro352Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000986 in 1,013,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P352A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0460
• Publications: 0 publications found

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

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=0.21286625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2	c.1054C>A	p.Pro352Thr	missense_variant	Exon 7 of 8	ENST00000393927.9	NP_001139647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9	c.1054C>A	p.Pro352Thr	missense_variant	Exon 7 of 8	1	NM_001146175.2	ENSP00000377504.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.86e-7 AC: 1 AN: 1013972 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 478188

African (AFR) AF: 0.00 AC: 0 AN: 20080

American (AMR) AF: 0.00 AC: 0 AN: 5986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10962

East Asian (EAS) AF: 0.00 AC: 0 AN: 19870

South Asian (SAS) AF: 0.00 AC: 0 AN: 19184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2556

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 874522

Other (OTH) AF: 0.00 AC: 0 AN: 38434

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.046
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.075
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Vest4		0.17
MutPred		0.27		Gain of phosphorylation at P352 (P = 0.0134);
MVP		0.52
MPC		0.55
ClinPred		0.83	D
GERP RS		4.1
gMVP		0.25
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs993166225; hg19: chr19-8575780;