1-77581777-T-C

Position:

• chr1-77581777-T-C

Variant summary

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

The ENST00000370801.8(ZZZ3):​c.1907A>G​(p.Gln636Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZZZ3 ENST00000370801.8 missense, splice_region
• Scores: Splicing: ADA: 0.9953
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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]

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
ZZZ3	NM_015534.6	c.1907A>G	p.Gln636Arg	missense_variant, splice_region_variant	8/15	ENST00000370801.8	NP_056349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZZZ3	ENST00000370801.8	c.1907A>G	p.Gln636Arg	missense_variant, splice_region_variant	8/15	1	NM_015534.6	ENSP00000359837	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 26, 2023

The c.1907A>G (p.Q636R) alteration is located in exon 8 (coding exon 4) of the ZZZ3 gene. This alteration results from a A to G substitution at nucleotide position 1907, causing the glutamine (Q) at amino acid position 636 to be replaced by an arginine (R). 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	0.19
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.25
Sift	Benign	0.042	D;T
Sift4G	Benign	0.30	T;T
Vest4		0.75
MutPred		0.11		Gain of MoRF binding (P = 0.0681);.;
MVP		0.31
MPC		0.60
ClinPred		0.76	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-78047462;