chr9-128731396-T-A

Variant names:

• chr9-128731396-T-A
• NM_006336.4:c.2244-2A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006336.4(ZER1):​c.2244-2A>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 28)
• Consequence: ZER1 NM_006336.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage

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.2244-2A>T		splice_acceptor intron	N/A	NP_006327.2
	ZER1	NM_001375954.1		c.2244-2A>T		splice_acceptor intron	N/A	NP_001362883.1	Q7Z7L7
	ZER1	NM_001375955.1		c.2244-2A>T		splice_acceptor intron	N/A	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.2244-2A>T		splice_acceptor intron	N/A	ENSP00000291900.2	Q7Z7L7
	ZER1	ENST00000960734.1		c.2271-2A>T		splice_acceptor intron	N/A	ENSP00000630793.1
	ZER1	ENST00000873659.1		c.2244-2A>T		splice_acceptor intron	N/A	ENSP00000543718.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.7
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.61		Position offset: -6
DS_AL_spliceai		0.79		Position offset: -2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-131493675;