chr19-9758419-G-A

Position:

• chr19-9758419-G-A

Variant summary

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

The ENST00000397902.7(ZNF846):​c.658C>T​(p.His220Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ZNF846 ENST00000397902.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

Genes affected

ZNF846 (HGNC:27260): (zinc finger protein 846) 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF846	NM_001077624.3	c.658C>T	p.His220Tyr	missense_variant	6/6	ENST00000397902.7	NP_001071092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF846	ENST00000397902.7	c.658C>T	p.His220Tyr	missense_variant	6/6	1	NM_001077624.3	ENSP00000380999	P1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151740 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151740 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74124

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

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

May 04, 2022

The c.658C>T (p.H220Y) alteration is located in exon 6 (coding exon 5) of the ZNF846 gene. This alteration results from a C to T substitution at nucleotide position 658, causing the histidine (H) at amino acid position 220 to be replaced by a tyrosine (Y). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;.;T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.76	.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Uncertain	0.097	D
MutationAssessor	Pathogenic	3.5	.;.;M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.7	.;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	.;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.38
MutPred		0.70		.;.;Gain of catalytic residue at H220 (P = 0.0172);
MVP		0.49
MPC		0.013
ClinPred		0.95	D
GERP RS		1.8
Varity_R		0.45
gMVP		0.032

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: rs1421903982; hg19: chr19-9869095;