19-57492206-C-T

Variant names:

• chr19-57492206-C-T
• rs769390022
• NM_024691.4:c.293C>T

Variant summary

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

The NM_024691.4(ZNF419):​c.293C>T​(p.Pro98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,754 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: ZNF419 NM_024691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.360
• Publications: 3 publications found

Genes affected

ZNF419 (HGNC:20648): (zinc finger protein 419) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000268107 (HGNC:):

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=0.06688741).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024691.4. 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
	ZNF419	NM_024691.4	MANE Select	c.293C>T	p.Pro98Leu	missense	Exon 4 of 5	NP_078967.3
	ZNF419	NM_001098491.2		c.296C>T	p.Pro99Leu	missense	Exon 4 of 5	NP_001091961.1	Q96HQ0-5
	ZNF419	NM_001098492.2		c.257C>T	p.Pro86Leu	missense	Exon 3 of 4	NP_001091962.1	Q96HQ0-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF419	ENST00000221735.12	TSL:1 MANE Select	c.293C>T	p.Pro98Leu	missense	Exon 4 of 5	ENSP00000221735.7	Q96HQ0-1
	ZNF419	ENST00000424930.6	TSL:1	c.296C>T	p.Pro99Leu	missense	Exon 4 of 5	ENSP00000388864.1	Q96HQ0-5
	ZNF419	ENST00000523439.1	TSL:1	n.1000C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151904 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 11 AN: 251488 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461850 Hom.: 0 Cov.: 37 AF XY: 0.0000371 AC XY: 27 AN XY: 727236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111974

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000329736), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151904 Hom.: 0 Cov.: 27 AF XY: 0.0000270 AC XY: 2 AN XY: 74184

African (AFR) AF: 0.00 AC: 0 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000806 Hom.: 0

ExAC AF: 0.0000330 AC: 4

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	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.7
DANN	Benign	0.21
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.36
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.014
Sift	Benign	0.70	T
Sift4G	Benign	0.70	T
Polyphen		0.0020	B
Vest4		0.15
MutPred		0.27		Loss of glycosylation at S95 (P = 0.0476)
MVP		0.099
MPC		0.028
ClinPred		0.020	T
GERP RS		0.76
Varity_R		0.031
gMVP		0.059
Mutation Taster		=98/2	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: rs769390022; hg19: chr19-58003574;