chr19-2933806-A-G

Variant names:

• chr19-2933806-A-G
• rs1381072665
• NM_021217.3:c.1321T>C

Variant summary

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

The NM_021217.3(ZNF77):​c.1321T>C​(p.Cys441Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C441G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF77 NM_021217.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.55
• Publications: 0 publications found

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

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, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021217.3. 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
	ZNF77	NM_021217.3	MANE Select	c.1321T>C	p.Cys441Arg	missense	Exon 4 of 4	NP_067040.1	Q15935
	ZNF77	NM_001426550.1		c.781T>C	p.Cys261Arg	missense	Exon 3 of 3	NP_001413479.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF77	ENST00000314531.5	TSL:1 MANE Select	c.1321T>C	p.Cys441Arg	missense	Exon 4 of 4	ENSP00000319053.3	Q15935
	ZNF77	ENST00000915162.1		c.1318T>C	p.Cys440Arg	missense	Exon 4 of 4	ENSP00000585221.1
	ZNF77	ENST00000863233.1		c.697T>C	p.Cys233Arg	missense	Exon 4 of 4	ENSP00000533292.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251094 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460962 Hom.: 0 Cov.: 78 AF XY: 0.00000138 AC XY: 1 AN XY: 726582

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111288

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		6.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-12	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.74		Gain of MoRF binding (P = 0.0161)
MVP		0.96
MPC		0.40
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.91
gMVP		0.13
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1381072665; hg19: chr19-2933804;