9-128731384-C-T

Variant names:

• chr9-128731384-C-T
• rs1457212628
• NM_006336.4:c.2254G>A

Variant summary

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

The NM_006336.4(ZER1):​c.2254G>A​(p.Glu752Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000745 in 134,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000075 (0 hom., cov: 30)
• Consequence: ZER1 NM_006336.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.66

Genes affected

ZER1 (HGNC:30960): (zyg-11 related cell cycle regulator) This gene encodes a subunit of an E3 ubiquitin ligase complex that may be involved in meiosis. The encoded protein contains three leucine-rich repeat motifs. [provided by RefSeq, Nov 2012]

ZDHHC12-DT (HGNC:55873): (ZDHHC12 divergent transcript)

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
ZER1	NM_006336.4	c.2254G>A	p.Glu752Lys	missense_variant	Exon 16 of 16	ENST00000291900.7	NP_006327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZER1	ENST00000291900.7	c.2254G>A	p.Glu752Lys	missense_variant	Exon 16 of 16	1	NM_006336.4	ENSP00000291900.2
ZDHHC12-DT	ENST00000443631.2	n.202-1458C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.00000745 AC: 1 AN: 134212 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000157

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000745 AC: 1 AN: 134212 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 64104

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000157

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2254G>A (p.E752K) alteration is located in exon 16 (coding exon 15) of the ZER1 gene. This alteration results from a G to A substitution at nucleotide position 2254, causing the glutamic acid (E) at amino acid position 752 to be replaced by a lysine (K). 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	0.13
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.35
Sift	Benign	0.090	T
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.50
MutPred		0.40		Gain of MoRF binding (P = 0.0019);
MVP		0.14
MPC		0.59
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.37
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1457212628; hg19: chr9-131493663;