19-22391757-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001098626.2(ZNF98):c.1478A>G(p.Glu493Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,602,474 control chromosomes in the GnomAD database, including 5 homozygotes. 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: 𝑓 0.00053 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: ZNF98 NM_001098626.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -6.56

Genes affected

ZNF98 (HGNC:13174): (zinc finger protein 98) 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, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00762406).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF98	NM_001098626.2	c.1478A>G	p.Glu493Gly	missense_variant	4/4	ENST00000357774.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF98	ENST00000357774.9	c.1478A>G	p.Glu493Gly	missense_variant	4/4	1	NM_001098626.2	P1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152128 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000235 AC: 341 AN: 1450346 Hom.: 3 Cov.: 33 AF XY: 0.000234 AC XY: 169 AN XY: 721276

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000280

Gnomad4 OTH exome AF: 0.000653

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152128 Hom.: 2 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.000528 Hom.: 0

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

Mar 01, 2023

The c.1478A>G (p.E493G) alteration is located in exon 4 (coding exon 4) of the ZNF98 gene. This alteration results from a A to G substitution at nucleotide position 1478, causing the glutamic acid (E) at amino acid position 493 to be replaced by a glycine (G). 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	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.013	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.025
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.047	D
Polyphen		0.032	B
Vest4		0.18
MVP		0.19
MPC		1.0
ClinPred		0.14	T
GERP RS		1.3
Varity_R		0.23
gMVP		0.015

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: rs774151116; hg19: chr19-22574559;