19-11948299-A-G

Position:

• chr19-11948299-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.275A>G​(p.Asn92Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,292 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: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ZNF700 NM_144566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.148

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=0.029982358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF700	NM_144566.3	c.275A>G	p.Asn92Ser	missense_variant	4/4	ENST00000254321.10	NP_653167.1
ZNF700	NM_001271848.2	c.284A>G	p.Asn95Ser	missense_variant	4/4		NP_001258777.1
ZNF69	XM_017027231.2	c.500-31742A>G		intron_variant			XP_016882720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF700	ENST00000254321.10	c.275A>G	p.Asn92Ser	missense_variant	4/4	1	NM_144566.3	ENSP00000254321.4
ENSG00000267179	ENST00000590798.1	c.63+23026A>G		intron_variant		2		ENSP00000467286.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000599 AC: 15 AN: 250398 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135402

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1460946 Hom.: 0 Cov.: 32 AF XY: 0.000131 AC XY: 95 AN XY: 726822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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

Nov 12, 2024

The c.275A>G (p.N92S) 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 275, causing the asparagine (N) at amino acid position 92 to be replaced by a serine (S). 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	0.077
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.15
DANN	Benign	0.83
DEOGEN2	Benign	0.00067	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.064	T;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.030	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.2	N;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.26	N;.;.
REVEL	Benign	0.0070
Sift	Benign	0.67	T;.;.
Sift4G	Benign	0.58	T;T;T
Polyphen		0.016	B;.;.
Vest4		0.047
MutPred		0.33		Gain of phosphorylation at N92 (P = 0.0104);.;.;
MVP		0.31
MPC		0.0087
ClinPred		0.037	T
GERP RS		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
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: rs141645705; hg19: chr19-12059114;