17-49312700-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001145365.3(ZNF652):c.1046T>G(p.Val349Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V349I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZNF652 NM_001145365.3 missense, splice_region
• Scores: Splicing: ADA: 0.6317
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

ZNF652 (HGNC:29147): (zinc finger protein 652) Predicted to enable DNA-binding transcription factor 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 by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FLJ40194 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF652	NM_001145365.3	c.1046T>G	p.Val349Gly	missense_variant, splice_region_variant	3/6	ENST00000430262.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF652	ENST00000430262.3	c.1046T>G	p.Val349Gly	missense_variant, splice_region_variant	3/6	1	NM_001145365.3	P1
ZNF652	ENST00000362063.6	c.1046T>G	p.Val349Gly	missense_variant, splice_region_variant	3/6	1		P1
FLJ40194	ENST00000655089.1	n.864-4891A>C		intron_variant, non_coding_transcript_variant
ZNF652	ENST00000508237.5	c.506T>G	p.Val169Gly	missense_variant, splice_region_variant, NMD_transcript_variant	4/8	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Dec 20, 2022

The c.1046T>G (p.V349G) alteration is located in exon 3 (coding exon 2) of the ZNF652 gene. This alteration results from a T to G substitution at nucleotide position 1046, causing the valine (V) at amino acid position 349 to be replaced by a glycine (G). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.42		Gain of disorder (P = 0.0285);Gain of disorder (P = 0.0285);
MVP		0.36
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.74
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-47390062;