9-96819061-C-T

Position:

• chr9-96819061-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001001662.3(ZNF782):​c.962G>A​(p.Arg321His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00668 in 1,614,118 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (47 hom.)
• Consequence: ZNF782 NM_001001662.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.30

Genes affected

ZNF782 (HGNC:33110): (zinc finger protein 782) Predicted to enable DNA-binding transcription activator 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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045799315).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00688 (10054/1461820) while in subpopulation MID AF= 0.0218 (126/5768). AF 95% confidence interval is 0.0187. There are 47 homozygotes in gnomad4_exome. There are 4919 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF782	NM_001001662.3	c.962G>A	p.Arg321His	missense_variant	6/6	ENST00000481138.6	NP_001001662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF782	ENST00000481138.6	c.962G>A	p.Arg321His	missense_variant	6/6	1	NM_001001662.3	ENSP00000419397	P1
ZNF782	ENST00000535338.5	c.962G>A	p.Arg321His	missense_variant	5/5	3		ENSP00000440624	P1
ZNF782	ENST00000289032.12	n.927G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 732 AN: 152180 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00525 AC: 1318 AN: 251162 Hom.: 5 AF XY: 0.00547 AC XY: 743 AN XY: 135740

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00330

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00781

Gnomad OTH exome AF: 0.00833

GnomAD4 exome AF: 0.00688 AC: 10054 AN: 1461820 Hom.: 47 Cov.: 33 AF XY: 0.00676 AC XY: 4919 AN XY: 727206

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00304

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00789

Gnomad4 OTH exome AF: 0.00632

GnomAD4 genome AF: 0.00481 AC: 732 AN: 152298 Hom.: 2 Cov.: 33 AF XY: 0.00477 AC XY: 355 AN XY: 74468

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00716

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00670 Hom.: 10

Bravo AF: 0.00551

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00485 AC: 589

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00911

EpiControl AF: 0.00907

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Mycotic Aneurysm, Intracranial Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Brain Center Rudolf Magnus, University Medical Center Utrecht

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.4
DANN	Benign	0.67
DEOGEN2	Benign	0.00086	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0	N
LIST_S2	Benign	0.31	.;T
M_CAP	Benign	0.00071	T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.61	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.2	N;.
REVEL	Benign	0.026
Sift	Benign	0.80	T;.
Sift4G	Benign	0.92	T;T
Polyphen		0.0	B;B
Vest4		0.034
MVP		0.17
MPC		0.13
ClinPred		0.00042	T
GERP RS		-0.25
Varity_R		0.018
gMVP		0.022

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: rs146058964; hg19: chr9-99581343;