chr19-57491527-G-T

Variant names:

• chr19-57491527-G-T
• rs1190332750
• NM_024691.4:c.129G>T

Variant summary

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

The NM_024691.4(ZNF419):​c.129G>T​(p.Leu43Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L43S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF419 NM_024691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.654
• Publications: 1 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: 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=0.23773012).

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.129G>T	p.Leu43Phe	missense	Exon 3 of 5	NP_078967.3
	ZNF419	NM_001098491.2		c.132G>T	p.Leu44Phe	missense	Exon 3 of 5	NP_001091961.1	Q96HQ0-5
	ZNF419	NM_001098492.2		c.93G>T	p.Leu31Phe	missense	Exon 2 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.129G>T	p.Leu43Phe	missense	Exon 3 of 5	ENSP00000221735.7	Q96HQ0-1
	ZNF419	ENST00000424930.6	TSL:1	c.132G>T	p.Leu44Phe	missense	Exon 3 of 5	ENSP00000388864.1	Q96HQ0-5
	ZNF419	ENST00000523439.1	TSL:1	n.321G>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251490 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 57 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

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: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-0.65
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.056	T
Polyphen		0.037	B
Vest4		0.33
MutPred		0.67		Loss of stability (P = 0.0601)
MVP		0.088
MPC		0.17
ClinPred		0.53	D
GERP RS		-0.90
Varity_R		0.12
gMVP		0.20
Mutation Taster		=97/3	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: rs1190332750; hg19: chr19-58002895;