17-49312700-A-C

Variant names:

• chr17-49312700-A-C
• NM_001145365.3:c.1046T>G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145365.3. 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
	ZNF652	NM_001145365.3	MANE Select	c.1046T>G	p.Val349Gly	missense splice_region	Exon 3 of 6	NP_001138837.1	Q9Y2D9
	ZNF652	NM_014897.2		c.1046T>G	p.Val349Gly	missense splice_region	Exon 3 of 6	NP_055712.1	Q9Y2D9
	ZNF652	NR_135579.2		n.1230T>G		splice_region non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF652	ENST00000430262.3	TSL:1 MANE Select	c.1046T>G	p.Val349Gly	missense splice_region	Exon 3 of 6	ENSP00000416305.2	Q9Y2D9
	ZNF652	ENST00000362063.6	TSL:1	c.1046T>G	p.Val349Gly	missense splice_region	Exon 3 of 6	ENSP00000354686.2	Q9Y2D9
	ZNF652	ENST00000949719.1		c.1100T>G	p.Val367Gly	missense splice_region	Exon 4 of 7	ENSP00000619778.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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	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
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.42		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

Other links and lift over

hg19: chr17-47390062;