chr1-52771597-A-C

Position:

• chr1-52771597-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_024646.3(ZYG11B):​c.774A>C​(p.Leu258Phe) variant causes a missense change involving the alteration of a non-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: 0.259

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZYG11B	NM_024646.3	c.774A>C	p.Leu258Phe	missense_variant	3/14	ENST00000294353.7
ZYG11B	XM_006710898.5	c.762A>C	p.Leu254Phe	missense_variant	3/14
ZYG11B	XM_017002336.3	c.774A>C	p.Leu258Phe	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZYG11B	ENST00000294353.7	c.774A>C	p.Leu258Phe	missense_variant	3/14	1	NM_024646.3	P1
ZYG11B	ENST00000545132.5	c.774A>C	p.Leu258Phe	missense_variant	3/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Apr 06, 2024

The c.774A>C (p.L258F) alteration is located in exon 3 (coding exon 3) of the ZYG11B gene. This alteration results from a A to C substitution at nucleotide position 774, causing the leucine (L) at amino acid position 258 to be replaced by a phenylalanine (F). 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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	.;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.14	T;T
Sift4G	Benign	0.17	T;T
Polyphen		1.0	.;D
Vest4		0.81
MutPred		0.73		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.17
MPC		2.1
ClinPred		0.94	D
GERP RS		-3.6
Varity_R		0.077
gMVP		0.54

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: chr1-53237269;