chr19-8511746-G-C

Variant names:

• chr19-8511746-G-C
• rs1006105412
• NM_001146175.2:c.745C>G

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.745C>G​(p.Pro249Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,302,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. P249T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.688
• 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=0.09742123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2	c.745C>G	p.Pro249Ala	missense_variant	Exon 5 of 8	ENST00000393927.9	NP_001139647.1
ZNF414	NM_032370.3	c.745C>G	p.Pro249Ala	missense_variant	Exon 5 of 6		NP_115746.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9	c.745C>G	p.Pro249Ala	missense_variant	Exon 5 of 8	1	NM_001146175.2	ENSP00000377504.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1302690 Hom.: 0 Cov.: 39 AF XY: 0.00000315 AC XY: 2 AN XY: 635722

African (AFR) AF: 0.0000378 AC: 1 AN: 26470

American (AMR) AF: 0.00 AC: 0 AN: 21308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18354

East Asian (EAS) AF: 0.00 AC: 0 AN: 33646

South Asian (SAS) AF: 0.0000154 AC: 1 AN: 64860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1043532

Other (OTH) AF: 0.00 AC: 0 AN: 53816

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.56
DEOGEN2	Benign	0.0042	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L
PhyloP100		0.69
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.079
Sift	Benign	0.35	T;T
Sift4G	Uncertain	0.025	D;D
Polyphen		0.22	.;B
Vest4		0.23
MutPred		0.33		Loss of glycosylation at P249 (P = 0.1251);Loss of glycosylation at P249 (P = 0.1251);
MVP		0.16
MPC		0.59
ClinPred		0.14	T
GERP RS		1.4
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.24
Mutation Taster		=95/5	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: rs1006105412; hg19: chr19-8576630;