10-180034-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001370100.5(ZMYND11):c.22C>T(p.Arg8Ter) variant causes a stop gained change. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZMYND11 NM_001370100.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.66

Genes affected

ZMYND11 (HGNC:16966): (zinc finger MYND-type containing 11) The protein encoded by this gene was first identified by its ability to bind the adenovirus E1A protein. The protein localizes to the nucleus. It functions as a transcriptional repressor, and expression of E1A inhibits this repression. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-180034-C-T is Pathogenic according to our data. Variant chr10-180034-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 393552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-180034-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZMYND11	NM_001370100.5	c.22C>T	p.Arg8Ter	stop_gained	2/15	ENST00000381604.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZMYND11	ENST00000381604.9	c.22C>T	p.Arg8Ter	stop_gained	2/15	5	NM_001370100.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 30 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000393552). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 13, 2021	de novo variant in an individual with Seizure/epilepsy/Rx: Absence seizures, onset 8-13y, GTC onset 15y. EEG: 3-3.5Hz generalised spike and wave. Neuropsych/development: Moderate LD, macrocephaly, speech delay, enuresis; normal CT head. Dysmorphism: Hypertelorism, broad forehead, flat nasal bridge, bilateral short fifth fingers, modified palmar crease -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2022	Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34216016) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 05, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 393552). This premature translational stop signal has been observed in individual(s) with clinical features of ZMYND11-related conditions (PMID: 34216016). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg8*) in the ZMYND11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZMYND11 are known to be pathogenic (PMID: 25217958). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.81, 0.73, 0.85, 0.82, 0.73, 0.73, 0.73, 0.85
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs1060499626; hg19: chr10-225974;