16-71475270-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006961.4(ZNF19):c.1277C>T(p.Ser426Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF19 NM_006961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.573

Genes affected

ZNF19 (HGNC:12981): (zinc finger protein 19) The protein encoded by this gene contains a zinc finger, a nucleic acid-binding domain present in many transcription factors. This gene is located in a region next to ZNF23, a gene also encoding a zinc finger protein, on chromosome 16. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13478282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF19	NM_006961.4	c.1277C>T	p.Ser426Phe	missense_variant	6/6	ENST00000288177.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF19	ENST00000288177.10	c.1277C>T	p.Ser426Phe	missense_variant	6/6	1	NM_006961.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251274 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461868 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

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

Jul 25, 2023

The c.1277C>T (p.S426F) alteration is located in exon 6 (coding exon 4) of the ZNF19 gene. This alteration results from a C to T substitution at nucleotide position 1277, causing the serine (S) at amino acid position 426 to be replaced by a phenylalanine (F). 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	Benign	0.26
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.;T
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-4.2	D;D;.;D
REVEL	Benign	0.077
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.11
MutPred		0.46		Loss of disorder (P = 0.0043);.;.;Loss of disorder (P = 0.0043);
MVP		0.40
MPC		0.26
ClinPred		0.79	D
GERP RS		2.9
Varity_R		0.36
gMVP		0.027

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

Publications

LitVar

Other links and lift over

dbSNP: rs761209018; hg19: chr16-71509173;