1-52821586-G-T

Position:

• chr1-52821586-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_024646.3(ZYG11B):​c.2192G>T​(p.Arg731Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZYG11B NM_024646.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

Genes affected

ZYG11B (HGNC:25820): (zyg-11 family member B, cell cycle regulator) Involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process and protein quality control for misfolded or incompletely synthesized proteins. Part of Cul2-RING ubiquitin ligase complex. [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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZYG11B. . Gene score misZ 3.9832 (greater than the threshold 3.09). Trascript score misZ 4.3282 (greater than threshold 3.09). GenCC has associacion of gene with multiple congenital anomalies/dysmorphic syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27250397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZYG11B	NM_024646.3	c.2192G>T	p.Arg731Met	missense_variant	14/14	ENST00000294353.7
ZYG11B	XM_006710898.5	c.2180G>T	p.Arg727Met	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZYG11B	ENST00000294353.7	c.2192G>T	p.Arg731Met	missense_variant	14/14	1	NM_024646.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 26, 2022

The c.2192G>T (p.R731M) alteration is located in exon 14 (coding exon 14) of the ZYG11B gene. This alteration results from a G to T substitution at nucleotide position 2192, causing the arginine (R) at amino acid position 731 to be replaced by a methionine (M). 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	0.23
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.040	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.94	D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		0.90	P
Vest4		0.45
MutPred		0.48		Gain of helix (P = 0.0496);
MVP		0.043
MPC		1.8
ClinPred		0.77	D
GERP RS		5.5
Varity_R		0.11
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-53287258;