rs1135401797

Variant names:

• chr10-180088-C-T
• rs1135401797
• NM_001370100.5:c.76C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001330057.3(ZMYND11):​c.-71C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,460,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZMYND11 NM_001330057.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.76

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-180088-C-T is Pathogenic according to our data. Variant chr10-180088-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMYND11	NM_001370100.5	c.76C>T	p.Arg26Trp	missense_variant	Exon 2 of 15	ENST00000381604.9	NP_001357029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMYND11	ENST00000381604.9	c.76C>T	p.Arg26Trp	missense_variant	Exon 2 of 15	5	NM_001370100.5	ENSP00000371017.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460928 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726784

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 24, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34216016, 28708303) -

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 26 of the ZMYND11 protein (p.Arg26Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ZMYND11-related conditions (PMID: 28708303). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 431123). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Intellectual disability, autosomal dominant 30 Pathogenic:1

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability; dysmorphism (hypertelorism ) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;T;.;T;.;T;.;.;T;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.8	.;L;L;.;L;L;.;L;.;L;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.2	D;D;D;.;D;D;D;.;D;.;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D;D;D;.;D;D;D;.;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.99	.;.;.;D;.;.;.;.;D;.;.;.
Vest4		0.92, 0.79, 0.79, 0.79, 0.89, 0.79, 0.80, 0.77, 0.77
MutPred		0.39		Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);Gain of ubiquitination at K29 (P = 0.0505);
MVP		0.77
MPC		2.4
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.98

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: rs1135401797; hg19: chr10-226028; COSMIC: COSV59081419;