chr8-144804148-C-A

Variant names:

• chr8-144804148-C-A
• rs775847712
• NM_213605.3:c.184C>A

Variant summary

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

The NM_213605.3(ZNF517):​c.184C>A​(p.Leu62Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,812 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: 0.0000021 (0 hom.)
• Consequence: ZNF517 NM_213605.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.66
• Publications: 0 publications found

Genes affected

ZNF517 (HGNC:27984): (zinc finger protein 517) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.14837423).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213605.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF517	NM_213605.3	MANE Select	c.184C>A	p.Leu62Met	missense	Exon 4 of 5	NP_998770.2	Q6ZMY9
	ZNF517	NM_001384904.1		c.184C>A	p.Leu62Met	missense	Exon 4 of 5	NP_001371833.1	Q6ZMY9
	ZNF517	NM_001384905.1		c.184C>A	p.Leu62Met	missense	Exon 5 of 6	NP_001371834.1	Q6ZMY9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF517	ENST00000359971.4	TSL:4 MANE Select	c.184C>A	p.Leu62Met	missense	Exon 4 of 5	ENSP00000353058.3	Q6ZMY9
	ZNF517	ENST00000529429.5	TSL:1	c.82C>A	p.Leu28Met	missense	Exon 2 of 3	ENSP00000432025.1	H0YCN3
	ZNF517	ENST00000525105.5	TSL:1	c.184C>A	p.Leu62Met	missense	Exon 3 of 4	ENSP00000433299.1	G3V191

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727200

⚠️ 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: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000096912), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-4.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.054
Sift	Benign	0.21	T
Sift4G	Benign	0.067	T
Polyphen		0.53	P
Vest4		0.12
MutPred		0.43		Loss of helix (P = 0.079)
MVP		0.072
MPC		0.66
ClinPred		0.58	D
GERP RS		-3.3
Varity_R		0.077
gMVP		0.067
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs775847712; hg19: chr8-146029533;