16-1998572-G-A

Position:

• chr16-1998572-G-A

Variant summary

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

The NM_001405664.1(ZNF598):​c.2405C>T​(p.Ala802Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF598 NM_001405664.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31

Genes affected

ZNF598 (HGNC:28079): (zinc finger protein 598, E3 ubiquitin ligase) Zinc-finger proteins bind nucleic acids and play important roles in various cellular functions, including cell proliferation, differentiation, and apoptosis. This protein and Grb10-interacting GYF protein 2 have been identified as a components of the mammalian 4EHP (m4EHP) complex. The complex is thought to function as a translation repressor in embryonic development. [provided by RefSeq, Oct 2012]

ZNF598 (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, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF598	NM_001405664.1	c.2405C>T	p.Ala802Val	missense_variant	14/14		NP_001392593.1
ZNF598	NM_178167.5	c.2375C>T	p.Ala792Val	missense_variant	14/14		NP_835461.2
ZNF598	NM_001405665.1	c.2357C>T	p.Ala786Val	missense_variant	14/14		NP_001392594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF598	ENST00000562103.2	c.2375C>T	p.Ala792Val	missense_variant	14/14	1		ENSP00000455308.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1407396 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 692792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 27, 2022

The c.2375C>T (p.A792V) alteration is located in exon 12 (coding exon 12) of the ZNF598 gene. This alteration results from a C to T substitution at nucleotide position 2375, causing the alanine (A) at amino acid position 792 to be replaced by a valine (V). 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
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.89	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D;D
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.83
MVP		0.39
ClinPred		0.98	D
GERP RS		3.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2048573;