19-8511682-C-A

Variant names:

• chr19-8511682-C-A
• rs777117024
• NM_001146175.2:c.809G>T

Variant summary

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

The NM_001146175.2(ZNF414):​c.809G>T​(p.Arg270Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,341,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R270H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146175.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF414	NM_001146175.2	MANE Select	c.809G>T	p.Arg270Leu	missense	Exon 5 of 8	NP_001139647.1	Q96IQ9-2
	ZNF414	NM_032370.3		c.809G>T	p.Arg270Leu	missense	Exon 5 of 6	NP_115746.2	Q96IQ9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF414	ENST00000393927.9	TSL:1 MANE Select	c.809G>T	p.Arg270Leu	missense	Exon 5 of 8	ENSP00000377504.3	Q96IQ9-2
	ZNF414	ENST00000255616.8	TSL:1	c.809G>T	p.Arg270Leu	missense	Exon 5 of 6	ENSP00000255616.7	Q96IQ9-1
	ZNF414	ENST00000593661.5	TSL:3	c.347G>T	p.Arg116Leu	missense	Exon 3 of 5	ENSP00000473079.1	M0R398

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1341752 Hom.: 0 Cov.: 39 AF XY: 0.00000152 AC XY: 1 AN XY: 658330

African (AFR) AF: 0.0000344 AC: 1 AN: 29070

American (AMR) AF: 0.00 AC: 0 AN: 24532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20080

East Asian (EAS) AF: 0.00 AC: 0 AN: 36190

South Asian (SAS) AF: 0.00 AC: 0 AN: 69546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1058808

Other (OTH) AF: 0.00 AC: 0 AN: 55470

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.14		Loss of methylation at R270 (P = 0.0315)
MVP		0.43
MPC		0.96
ClinPred		0.97	D
GERP RS		4.5
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.46
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs777117024; hg19: chr19-8576566;