chr19-20948746-A-G

Variant names:

• chr19-20948746-A-G
• rs193252937
• NM_003429.5:c.232A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003429.5(ZNF85):​c.232A>G​(p.Met78Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,542,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ZNF85 NM_003429.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049731433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF85	NM_003429.5	c.232A>G	p.Met78Val	missense_variant, splice_region_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.232A>G	p.Met78Val	missense_variant, splice_region_variant	Exon 4 of 4	1	NM_003429.5	ENSP00000329793.7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152066 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000248 AC: 5 AN: 201364 AF XY: 0.00000925

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000529

Gnomad NFE exome AF: 0.0000309

Gnomad OTH exome AF: 0.000214

GnomAD4 exome AF: 0.0000137 AC: 19 AN: 1390332 Hom.: 0 Cov.: 29 AF XY: 0.0000117 AC XY: 8 AN XY: 685494

African (AFR) AF: 0.00 AC: 0 AN: 30864

American (AMR) AF: 0.00 AC: 0 AN: 32510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21956

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39090

South Asian (SAS) AF: 0.00 AC: 0 AN: 71608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1080574

Other (OTH) AF: 0.0000349 AC: 2 AN: 57338

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74408

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232A>G (p.M78V) 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 232, causing the methionine (M) at amino acid position 78 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	0.079
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.059
DANN	Benign	0.26
DEOGEN2	Benign	0.0073	.;.;T;.;.;.;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.60	T;T;T;T;T;D;T;D;T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.038	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.84	.;.;L;.;.;.;.;.;.
PhyloP100		-1.8
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.91	.;.;N;.;N;.;.;.;.
REVEL	Benign	0.0070
Sift	Benign	0.35	.;.;T;.;T;.;.;.;.
Sift4G	Benign	0.74	T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;B;.;B;.;.;.;.
Vest4		0.10, 0.088
MVP		0.12
MPC		0.0040
ClinPred		0.050	T
GERP RS		-2.1
Varity_R		0.032
gMVP		0.041
Mutation Taster		=94/6	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: rs193252937; hg19: chr19-21131552;