19-20948770-C-G

Variant names:

• chr19-20948770-C-G
• rs1273775236
• NM_003429.5:c.256C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003429.5(ZNF85):​c.256C>G​(p.Leu86Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000885 in 1,581,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: ZNF85 NM_003429.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00100
• 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09301379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF85	NM_003429.5	c.256C>G	p.Leu86Val	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.256C>G	p.Leu86Val	missense_variant	Exon 4 of 4	1	NM_003429.5	ENSP00000329793.7

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151980 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 229030 AF XY: 0.0000161

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000629 AC: 9 AN: 1429864 Hom.: 0 Cov.: 32 AF XY: 0.00000847 AC XY: 6 AN XY: 708800

African (AFR) AF: 0.000248 AC: 8 AN: 32208

American (AMR) AF: 0.00 AC: 0 AN: 39872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24280

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.00 AC: 0 AN: 78938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097996

Other (OTH) AF: 0.0000169 AC: 1 AN: 59040

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151980 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74220

African (AFR) AF: 0.000121 AC: 5 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67924

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.256C>G (p.L86V) alteration is located in exon 4 (coding exon 4) of the ZNF85 gene. This alteration results from a C to G substitution at nucleotide position 256, causing the leucine (L) at amino acid position 86 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	0.080
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.4
DANN	Benign	0.93
DEOGEN2	Benign	0.022	.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.00069	T
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	.;.;M;.;.;.;.;.;.
PhyloP100		-0.0010
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	.;.;N;.;N;.;.;.;.
REVEL	Benign	0.038
Sift	Benign	0.072	.;.;T;.;T;.;.;.;.
Sift4G	Uncertain	0.039	D;D;T;D;T;D;D;D;D
Polyphen		0.60, 0.38	.;.;P;.;B;.;.;.;.
Vest4		0.086, 0.15
MutPred		0.32		.;.;Gain of catalytic residue at L86 (P = 0.1462);.;.;.;.;.;.;
MVP		0.13
MPC		0.0062
ClinPred		0.070	T
GERP RS		-0.84
Varity_R		0.093
gMVP		0.013
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: rs1273775236; hg19: chr19-21131576;