chr17-49298828-T-C

Variant names:

• chr17-49298828-T-C
• NM_001145365.3:c.1406A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001145365.3(ZNF652):​c.1406A>G​(p.Tyr469Cys) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZNF652 NM_001145365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF652	NM_001145365.3	c.1406A>G	p.Tyr469Cys	missense_variant	Exon 6 of 6	ENST00000430262.3	NP_001138837.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF652	ENST00000430262.3	c.1406A>G	p.Tyr469Cys	missense_variant	Exon 6 of 6	1	NM_001145365.3	ENSP00000416305.2
ZNF652	ENST00000362063.6	c.1406A>G	p.Tyr469Cys	missense_variant	Exon 6 of 6	1		ENSP00000354686.2
ZNF652	ENST00000508237.5	n.866A>G		non_coding_transcript_exon_variant	Exon 7 of 8	2		ENSP00000424848.1
FLJ40194	ENST00000655089.1	n.863+8332T>C		intron_variant	Intron 4 of 5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1406A>G (p.Y469C) alteration is located in exon 6 (coding exon 5) of the ZNF652 gene. This alteration results from a A to G substitution at nucleotide position 1406, causing the tyrosine (Y) at amino acid position 469 to be replaced by a cysteine (C). 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	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		8.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.65		Gain of disorder (P = 0.0286);Gain of disorder (P = 0.0286);
MVP		0.50
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.84
gMVP		0.86

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

hg19: chr17-47376190;