19-11948283-A-G

Position:

• chr19-11948283-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144566.3(ZNF700):​c.259A>G​(p.Ile87Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ZNF700 NM_144566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.202

Genes affected

ZNF700 (HGNC:25292): (zinc finger protein 700) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription 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]

ENSG00000267179 (HGNC:):

ZNF69 (HGNC:13138): (zinc finger protein 69) Enables identical protein binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056504756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF700	NM_144566.3	c.259A>G	p.Ile87Val	missense_variant	4/4	ENST00000254321.10	NP_653167.1
ZNF700	NM_001271848.2	c.268A>G	p.Ile90Val	missense_variant	4/4		NP_001258777.1
ZNF69	XM_017027231.2	c.500-31758A>G		intron_variant			XP_016882720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF700	ENST00000254321.10	c.259A>G	p.Ile87Val	missense_variant	4/4	1	NM_144566.3	ENSP00000254321.4
ENSG00000267179	ENST00000590798.1	c.63+23010A>G		intron_variant		2		ENSP00000467286.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460588 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726690

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Sep 30, 2024

The c.259A>G (p.I87V) alteration is located in exon 4 (coding exon 4) of the ZNF700 gene. This alteration results from a A to G substitution at nucleotide position 259, causing the isoleucine (I) at amino acid position 87 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.24
DANN	Benign	0.90
DEOGEN2	Benign	0.0017	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.35	T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.79	N;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.10	N;.;.
REVEL	Benign	0.059
Sift	Benign	0.95	T;.;.
Sift4G	Benign	0.61	T;T;T
Polyphen		0.017	B;.;.
Vest4		0.061
MutPred		0.21		Gain of ubiquitination at K90 (P = 0.0853);.;.;
MVP		0.081
MPC		0.0087
ClinPred		0.045	T
GERP RS		0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.0057

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: rs986017077; hg19: chr19-12059098;