8-144804217-G-A

Position:

• chr8-144804217-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_213605.3(ZNF517):​c.253G>A​(p.Ala85Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: ZNF517 NM_213605.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.48

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062604904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF517	NM_213605.3	c.253G>A	p.Ala85Thr	missense_variant	4/5	ENST00000359971.4	NP_998770.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF517	ENST00000359971.4	c.253G>A	p.Ala85Thr	missense_variant	4/5	4	NM_213605.3	ENSP00000353058	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.253G>A (p.A85T) alteration is located in exon 4 (coding exon 3) of the ZNF517 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the alanine (A) at amino acid position 85 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	0.080
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.025
DANN	Benign	0.49
DEOGEN2	Benign	0.0055	T;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.24	T;T;.;T
M_CAP	Benign	0.00068	T
MetaRNN	Benign	0.063	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;.;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.020	N;N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.35	T;T;T;T
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.020
MutPred		0.24		Gain of phosphorylation at A85 (P = 0.082);.;Gain of phosphorylation at A85 (P = 0.082);Gain of phosphorylation at A85 (P = 0.082);
MVP		0.092
MPC		0.26
ClinPred		0.12	T
GERP RS		-5.7
Varity_R		0.031
gMVP		0.057

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

LitVar

Other links and lift over

dbSNP: rs989656083; hg19: chr8-146029602;