19-57491489-G-T

Position:

• chr19-57491489-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024691.4(ZNF419):​c.91G>T​(p.Asp31Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ZNF419 NM_024691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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]

ZNF419 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF419	NM_024691.4	c.91G>T	p.Asp31Tyr	missense_variant	3/5	ENST00000221735.12	NP_078967.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF419	ENST00000221735.12	c.91G>T	p.Asp31Tyr	missense_variant	3/5	1	NM_024691.4	ENSP00000221735.7
ENSG00000268107	ENST00000601674.6	n.52G>T		non_coding_transcript_exon_variant	2/6	2		ENSP00000471625.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.94G>T (p.D32Y) alteration is located in exon 3 (coding exon 3) of the ZNF419 gene. This alteration results from a G to T substitution at nucleotide position 94, causing the aspartic acid (D) at amino acid position 32 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;.;.;.;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T;D;T;T;D;D;T;T;T;T;D;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	5.3	.;.;.;.;.;.;.;.;.;.;.;H;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-8.2	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.76
MutPred		0.78		.;.;.;.;.;.;.;.;Gain of sheet (P = 0.0221);.;.;Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);
MVP		0.40
MPC		0.18
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.83
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-58002857;