NM_024646.3:c.955T>C

Variant names:

• chr1-52779856-T-C
• NM_024646.3:c.955T>C

Variant summary

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

The NM_024646.3(ZYG11B):​c.955T>C​(p.Ser319Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S319C) has been classified 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: 5.21

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZYG11B	NM_024646.3	c.955T>C	p.Ser319Pro	missense_variant	Exon 4 of 14	ENST00000294353.7	NP_078922.1
ZYG11B	XM_006710898.5	c.943T>C	p.Ser315Pro	missense_variant	Exon 4 of 14		XP_006710961.1
ZYG11B	XM_017002336.3	c.955T>C	p.Ser319Pro	missense_variant	Exon 4 of 11		XP_016857825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZYG11B	ENST00000294353.7	c.955T>C	p.Ser319Pro	missense_variant	Exon 4 of 14	1	NM_024646.3	ENSP00000294353.6
ZYG11B	ENST00000545132.5	c.955T>C	p.Ser319Pro	missense_variant	Exon 4 of 14	2		ENSP00000441315.1

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

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.955T>C (p.S319P) alteration is located in exon 4 (coding exon 4) of the ZYG11B gene. This alteration results from a T to C substitution at nucleotide position 955, causing the serine (S) at amino acid position 319 to be replaced by a proline (P). 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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0098	T
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.95	.;P
Vest4		0.87
MutPred		0.35		Loss of glycosylation at S319 (P = 0.0337);Loss of glycosylation at S319 (P = 0.0337);
MVP		0.043
MPC		2.1
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.52
gMVP		0.71

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: chr1-53245528; COSMIC: COSV53749531;