chr19-20949173-A-G

Variant names:

• chr19-20949173-A-G
• rs1360534809
• NM_003429.5:c.659A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003429.5(ZNF85):​c.659A>G​(p.His220Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,442 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: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZNF85 NM_003429.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78
• Publications: 0 publications found

Genes affected

ZNF85 (HGNC:13160): (zinc finger protein 85) Enables DNA-binding transcription repressor 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. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000298806 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF85	NM_003429.5	c.659A>G	p.His220Arg	missense_variant	Exon 4 of 4	ENST00000328178.13	NP_003420.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF85	ENST00000328178.13	c.659A>G	p.His220Arg	missense_variant	Exon 4 of 4	1	NM_003429.5	ENSP00000329793.7

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461290 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 726956

African (AFR) AF: 0.0000598 AC: 2 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111810

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

African (AFR) AF: 0.0000482 AC: 2 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67954

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.659A>G (p.H220R) alteration is located in exon 4 (coding exon 4) of the ZNF85 gene. This alteration results from a A to G substitution at nucleotide position 659, causing the histidine (H) at amino acid position 220 to be replaced by an arginine (R). 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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T;.;.;.;.
Eigen	Benign	-0.0014
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.13	T;T;T;T;T
M_CAP	Benign	0.0014	T
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;.
PhyloP100		3.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.3	D;D;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0090	D;D;.;.;.
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		0.99	D;B;.;.;.
Vest4		0.17
MutPred		0.76		Gain of MoRF binding (P = 0.0311);.;.;.;.;
MVP		0.87
MPC		0.0059
ClinPred		0.91	D
GERP RS		1.3
Varity_R		0.33
gMVP		0.050
Mutation Taster		=98/2	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: rs1360534809; hg19: chr19-21131979;