chr19-20949787-C-A

Variant names:

• chr19-20949787-C-A
• NM_003429.5:c.1273C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003429.5(ZNF85):​c.1273C>A​(p.Pro425Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF85 NM_003429.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19086432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF85	NM_003429.5	c.1273C>A	p.Pro425Thr	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.1273C>A	p.Pro425Thr	missense_variant	Exon 4 of 4	1	NM_003429.5	ENSP00000329793.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459528 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726006

⚠️ 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: 33316

American (AMR) AF: 0.00 AC: 0 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85936

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110936

Other (OTH) AF: 0.00 AC: 0 AN: 60264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1273C>A (p.P425T) alteration is located in exon 4 (coding exon 4) of the ZNF85 gene. This alteration results from a C to A substitution at nucleotide position 1273, causing the proline (P) at amino acid position 425 to be replaced by a threonine (T). 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	0.34
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.12	T;T;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-6.9	D;D;.
REVEL	Benign	0.093
Sift	Uncertain	0.013	D;D;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;P;.
Vest4		0.099
MutPred		0.37		Loss of catalytic residue at P425 (P = 0.0317);.;.;
MVP		0.33
MPC		0.0091
ClinPred		0.87	D
GERP RS		0.10
Varity_R		0.28
gMVP		0.013
Mutation Taster		=93/7	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

hg19: chr19-21132593;