19-22391705-C-T

Variant names:

• chr19-22391705-C-T
• rs200235405
• NM_001098626.2:c.1530G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001098626.2(ZNF98):​c.1530G>A​(p.Met510Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,610,424 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M510V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (6 hom.)
• Consequence: ZNF98 NM_001098626.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.07
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005903244).
• BP6: Variant 19-22391705-C-T is Benign according to our data. Variant chr19-22391705-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2363153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098626.2. 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
	ZNF98	NM_001098626.2	MANE Select	c.1530G>A	p.Met510Ile	missense	Exon 4 of 4	NP_001092096.1	A6NK75

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF98	ENST00000357774.9	TSL:1 MANE Select	c.1530G>A	p.Met510Ile	missense	Exon 4 of 4	ENSP00000350418.4	A6NK75

Frequencies

GnomAD3 genomes AF: 0.000576 AC: 86 AN: 149374 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.0198

Gnomad EAS AF: 0.000204

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00195

GnomAD2 exomes AF: 0.000133 AC: 33 AN: 248072 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000402 AC: 587 AN: 1460936 Hom.: 6 Cov.: 32 AF XY: 0.000396 AC XY: 288 AN XY: 726782

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 429 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111532

Other (OTH) AF: 0.00128 AC: 77 AN: 60324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000575 AC: 86 AN: 149488 Hom.: 2 Cov.: 32 AF XY: 0.000575 AC XY: 42 AN XY: 73008

African (AFR) AF: 0.0000245 AC: 1 AN: 40756

American (AMR) AF: 0.0000663 AC: 1 AN: 15082

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 68 AN: 3428

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4890

South Asian (SAS) AF: 0.00 AC: 0 AN: 4620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67064

Other (OTH) AF: 0.00193 AC: 4 AN: 2074

Alfa AF: 0.000720 Hom.: 1

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.17
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.79
DANN	Benign	0.39
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00045	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.014
Sift	Benign	0.50	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.070
MutPred		0.54		Gain of methylation at K509 (P = 0.0236)
MVP		0.13
MPC		0.96
ClinPred		0.014	T
GERP RS		0.069
Varity_R		0.046
gMVP		0.011
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: rs200235405; hg19: chr19-22574507; COSMIC: COSV63338655; COSMIC: COSV63338655;