NM_001146175.2:c.841G>A

Variant names:

• chr19-8511650-C-T
• rs1487305573
• NM_001146175.2:c.841G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001146175.2(ZNF414):​c.841G>A​(p.Ala281Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,349,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ZNF414 NM_001146175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.426
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045824707).

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.841G>A	p.Ala281Thr	missense	Exon 5 of 8	NP_001139647.1	Q96IQ9-2
	ZNF414	NM_032370.3		c.841G>A	p.Ala281Thr	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.841G>A	p.Ala281Thr	missense	Exon 5 of 8	ENSP00000377504.3	Q96IQ9-2
	ZNF414	ENST00000255616.8	TSL:1	c.841G>A	p.Ala281Thr	missense	Exon 5 of 6	ENSP00000255616.7	Q96IQ9-1
	ZNF414	ENST00000593661.5	TSL:3	c.379G>A	p.Ala127Thr	missense	Exon 3 of 5	ENSP00000473079.1	M0R398

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000905 AC: 1 AN: 110468 AF XY: 0.0000168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000996

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1349946 Hom.: 0 Cov.: 40 AF XY: 0.00000151 AC XY: 1 AN XY: 662926

African (AFR) AF: 0.00 AC: 0 AN: 29378

American (AMR) AF: 0.00 AC: 0 AN: 25416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20392

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36378

South Asian (SAS) AF: 0.00 AC: 0 AN: 70566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061746

Other (OTH) AF: 0.00 AC: 0 AN: 55736

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.43
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.020
Sift	Benign	0.28	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.099
MutPred		0.15		Gain of phosphorylation at A281 (P = 0.0069)
MVP		0.25
MPC		0.22
ClinPred		0.030	T
GERP RS		-3.3
PromoterAI		0.0067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.072
gMVP		0.35
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1487305573; hg19: chr19-8576534;