9-111527573-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_133464.5(ZNF483):c.178T>C(p.Tyr60His) variant causes a missense change. 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: 32)
• Consequence: ZNF483 NM_133464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36

Genes affected

ZNF483 (HGNC:23384): (zinc finger protein 483) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF483	NM_133464.5	c.178T>C	p.Tyr60His	missense_variant	2/6	ENST00000309235.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF483	ENST00000309235.6	c.178T>C	p.Tyr60His	missense_variant	2/6	1	NM_133464.5	P1
ZNF483	ENST00000355824.7	c.178T>C	p.Tyr60His	missense_variant	2/6	1
ZNF483	ENST00000358151.8	c.178T>C	p.Tyr60His	missense_variant	2/6	2
ZNF483	ENST00000374374.3	c.178T>C	p.Tyr60His	missense_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 10, 2023

The c.178T>C (p.Y60H) alteration is located in exon 2 (coding exon 1) of the ZNF483 gene. This alteration results from a T to C substitution at nucleotide position 178, causing the tyrosine (Y) at amino acid position 60 to be replaced by a histidine (H). 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	0.66
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.6	H;.;.;H
MutationTaster	Benign	0.57	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.66
MutPred		0.83		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.41
MPC		1.3
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-114289853;