19-2933590-T-G

Variant names:

• chr19-2933590-T-G
• rs2088362944
• NM_021217.3:c.1537A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021217.3(ZNF77):​c.1537A>C​(p.Thr513Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ZNF77 NM_021217.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.794

Genes affected

ZNF77 (HGNC:13150): (zinc finger protein 77) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2524839).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF77	NM_021217.3	c.1537A>C	p.Thr513Pro	missense_variant	Exon 4 of 4	ENST00000314531.5	NP_067040.1
ZNF77	NM_001426550.1	c.997A>C	p.Thr333Pro	missense_variant	Exon 3 of 3		NP_001413479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF77	ENST00000314531.5	c.1537A>C	p.Thr513Pro	missense_variant	Exon 4 of 4	1	NM_021217.3	ENSP00000319053.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461738 Hom.: 0 Cov.: 77 AF XY: 0.00000275 AC XY: 2 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1537A>C (p.T513P) alteration is located in exon 4 (coding exon 4) of the ZNF77 gene. This alteration results from a A to C substitution at nucleotide position 1537, causing the threonine (T) at amino acid position 513 to be replaced by a proline (P). 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	0.81
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.00040	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.041
Sift	Benign	0.051	T
Sift4G	Uncertain	0.015	D
Polyphen		0.86	P
Vest4		0.18
MutPred		0.63		Loss of catalytic residue at T513 (P = 0.0266);
MVP		0.25
MPC		0.25
ClinPred		0.45	T
GERP RS		1.5
Varity_R		0.66
gMVP		0.10

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: rs2088362944; hg19: chr19-2933588;