9-128733427-G-A

Variant names:

• chr9-128733427-G-A
• rs774299730
• NM_006336.4:c.2242C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006336.4(ZER1):​c.2242C>T​(p.Arg748Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R748R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ZER1 NM_006336.4 missense, splice_region
• Scores: Splicing: ADA: 0.9904
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006336.4. 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
	ZER1	NM_006336.4	MANE Select	c.2242C>T	p.Arg748Cys	missense splice_region	Exon 15 of 16	NP_006327.2
	ZER1	NM_001375954.1		c.2242C>T	p.Arg748Cys	missense splice_region	Exon 15 of 16	NP_001362883.1	Q7Z7L7
	ZER1	NM_001375955.1		c.2242C>T	p.Arg748Cys	missense splice_region	Exon 15 of 16	NP_001362884.1	Q7Z7L7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZER1	ENST00000291900.7	TSL:1 MANE Select	c.2242C>T	p.Arg748Cys	missense splice_region	Exon 15 of 16	ENSP00000291900.2	Q7Z7L7
	ZER1	ENST00000960734.1		c.2269C>T	p.Arg757Cys	missense splice_region	Exon 15 of 16	ENSP00000630793.1
	ZER1	ENST00000873659.1		c.2242C>T	p.Arg748Cys	missense splice_region	Exon 17 of 18	ENSP00000543718.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152052 Hom.: 0 Cov.: 31

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250732 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461414 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111776

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152052 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000287 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Benign	0.10
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
Polyphen		0.98	D
Vest4		0.71
MutPred		0.42		Gain of catalytic residue at M746 (P = 0.001)
MVP		0.17
MPC		0.38
ClinPred		0.84	D
GERP RS		5.8
Varity_R		0.17
gMVP		0.54
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.79
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

Other links and lift over

dbSNP: rs774299730; hg19: chr9-131495706; COSMIC: COSV99402247; COSMIC: COSV99402247;