chr5-179033491-A-G

Variant names:

• chr5-179033491-A-G
• rs185712748
• NM_001136116.3:c.1543A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001136116.3(ZNF879):​c.1543A>G​(p.Lys515Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,562,542 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: ZNF879 NM_001136116.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.283

Genes affected

ZNF879 (HGNC:37273): (zinc finger protein 879) This gene encodes a kruppel-associated box-containing zinc finger protein (KRAB-ZFP). The encoded protein contains an N-terminal kruppel-associated box (KRAB) domain and thirteen C-terminal C2H2-type zinc finger domains. The KRAB-ZFPs represent the largest family of mammalian transcriptional repressors, which function through the recruitment of the nuclear co-factor KRAB-Associated Protein 1 (KAP1), to engage histone modifiers and induce heterochromatin formation. [provided by RefSeq, Jul 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047001243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF879	NM_001136116.3	c.1543A>G	p.Lys515Glu	missense_variant	Exon 5 of 5	ENST00000444149.7	NP_001129588.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF879	ENST00000444149.7	c.1543A>G	p.Lys515Glu	missense_variant	Exon 5 of 5	1	NM_001136116.3	ENSP00000414887.2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

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: 0.000105 AC: 18 AN: 172052 AF XY: 0.0000548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00139

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000362 AC: 51 AN: 1410194 Hom.: 1 Cov.: 32 AF XY: 0.0000287 AC XY: 20 AN XY: 696704

African (AFR) AF: 0.0000314 AC: 1 AN: 31802

American (AMR) AF: 0.0000272 AC: 1 AN: 36802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.00135 AC: 49 AN: 36378

South Asian (SAS) AF: 0.00 AC: 0 AN: 80072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085494

Other (OTH) AF: 0.00 AC: 0 AN: 58504

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74504

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

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

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000156 AC: 18

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1543A>G (p.K515E) alteration is located in exon 5 (coding exon 4) of the ZNF879 gene. This alteration results from a A to G substitution at nucleotide position 1543, causing the lysine (K) at amino acid position 515 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.10	N
PhyloP100		-0.28
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.011
Sift	Benign	0.13	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.085
MVP		0.048
MPC		0.19
ClinPred		0.016	T
GERP RS		1.9
Varity_R		0.12
gMVP		0.027
Mutation Taster		=100/0	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

Publications

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Other links and lift over

dbSNP: rs185712748; hg19: chr5-178460492;