Variant 1-77578790-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015534.6(ZZZ3):c.2162A>G(p.Tyr721Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000045 in 1,555,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

ZZZ3
NM_015534.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75

Variant links:

Genes affected

ZZZ3 (HGNC:24523): (zinc finger ZZ-type containing 3) Predicted to enable DNA binding activity and zinc ion binding activity. Predicted to be involved in histone H4 acetylation. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZZZ3 links:

ZZZ3 (HGNC:):

ZZZ3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09828067).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZZZ3	NM_015534.6 linkuse as main transcript	c.2162A>G	p.Tyr721Cys	missense_variant	11/15	ENST00000370801.8	NP_056349.1	Q8IYH5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZZZ3	ENST00000370801.8 linkuse as main transcript	c.2162A>G	p.Tyr721Cys	missense_variant	11/15	1	NM_015534.6	ENSP00000359837.3	Q8IYH5-1
ZZZ3	ENST00000370798.5 linkuse as main transcript	c.680A>G	p.Tyr227Cys	missense_variant	10/14	1		ENSP00000359834.1	Q8IYH5-3
ZZZ3	ENST00000481346.5 linkuse as main transcript	n.726A>G		non_coding_transcript_exon_variant	7/11	1
ZZZ3	ENST00000476275.5 linkuse as main transcript	n.3053A>G		non_coding_transcript_exon_variant	6/10	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000482

AC:

AN:

207590

Hom.:

AF XY:

0.00000883

AC XY:

AN XY:

113314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000428

AC:

AN:

1403154

Hom.:

Cov.:

AF XY:

0.00000430

AC XY:

AN XY:

697344

show subpopulations

Gnomad4 AFR exome

AF:

0.0000332

Gnomad4 AMR exome

AF:

0.0000585

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:

0.00000276

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.2162A>G (p.Y721C) alteration is located in exon 11 (coding exon 7) of the ZZZ3 gene. This alteration results from a A to G substitution at nucleotide position 2162, causing the tyrosine (Y) at amino acid position 721 to be replaced by a cysteine (C). 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

Benign

0.087

BayesDel_addAF

Benign

0.0026

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.11

Eigen_PC

Benign

0.098

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.0039

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.061

Sift

Benign

0.22

T;T

Sift4G

Benign

0.19

T;T

Vest4

0.36

MutPred

0.29

Loss of phosphorylation at Y721 (P = 0.0428);.;

MVP

0.043

MPC

0.92

ClinPred

0.69

GERP RS

5.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over