1-52813663-A-G

Variant names:

• chr1-52813663-A-G
• NM_024646.3:c.1823A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024646.3(ZYG11B):​c.1823A>G​(p.His608Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 8.61
• Publications: 0 publications found

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]

ZYG11B Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024646.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZYG11B	NM_024646.3	MANE Select	c.1823A>G	p.His608Arg	missense	Exon 11 of 14	NP_078922.1	Q9C0D3-1
	ZYG11B	NM_001441954.1		c.1811A>G	p.His604Arg	missense	Exon 12 of 15	NP_001428883.1
	ZYG11B	NR_199864.1		n.2167A>G		non_coding_transcript_exon	Exon 13 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZYG11B	ENST00000294353.7	TSL:1 MANE Select	c.1823A>G	p.His608Arg	missense	Exon 11 of 14	ENSP00000294353.6	Q9C0D3-1
	ZYG11B	ENST00000884648.1		c.1820A>G	p.His607Arg	missense	Exon 11 of 14	ENSP00000554707.1
	ZYG11B	ENST00000959293.1		c.1772A>G	p.His591Arg	missense	Exon 10 of 13	ENSP00000629352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.69		Gain of MoRF binding (P = 0.0075)
MVP		0.36
MPC		1.3
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.88
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr1-53279335;